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Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Scope
The Atlas of Genetics and Cytogenetics in Oncology and Haematology is a peer reviewed on-line journal in open
access, devoted to genes, cytogenetics, and clinical entities in cancer, and cancer-prone diseases.
It presents structured review articles (“cards”) on genes, leukaemias, solid tumours, cancer-prone diseases, and also
more traditional review articles (“deep insights”) on the above subjects and on surrounding topics.
It also present case reports in hematology and educational items in the various related topics for students in Medicine
and in Sciences.
Editorial correspondance
Jean-Loup Huret
Genetics, Department of Medical Information,
University Hospital
F-86021 Poitiers, France
tel +33 5 49 44 45 46 or +33 5 49 45 47 67
[email protected] or [email protected]
The Atlas of Genetics and Cytogenetics in Oncology and Haematology is published 2 times a year by ARMGHM, a
non profit organisation.
Philippe Dessen is the Database Director, and Alain Bernheim the Chairman of the on-line version (Gustave Roussy
Institute – Villejuif – France).
http://AtlasGeneticsOncology.org
© ATLAS - ISSN 1768-3262
The PDF version of the Atlas of Genetics and Cytogenetics in Oncology and Haematology is a reissue of the original articles published in collaboration with the
Institute for Scientific and Technical Information (INstitut de l’Information Scientifique et Technique - INIST) of the French National Center for Scientific Research
(CNRS) on its electronic publishing platform I-Revues.
Online and PDF versions of the Atlas of Genetics and Cytogenetics in Oncology and Haematology are hosted by INIST-CNRS.
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Editor
Jean-Loup Huret
(Poitiers, France)
Volume 1, Number 2, October - December 1997
Table of contents
Gene Section
ABL (v-abl Abelson murine leukemia viral oncogene homolog 1)
Jean-Loup Huret
40
BCR (breakpoint cluster region)
Jean-Loup Huret
43
ETO (eigth twenty one)
Jean-Loup Huret
46
MN1 (meningioma 1)
Jean-Loup Huret
48
PBX1 (pre-B-cell leukemia homeobox 1)
Jean-Loup Huret
49
AF10 (ALL1 fused gene from chromosome 10)
Jean-Loup Huret
51
AF17 (ALL1 fused gene from chromosome 17)
Jean-Loup Huret
53
AF4 (ALL1 fused gene from chromosome 4)
Jean-Loup Huret
54
AF6 (ALL1 fused gene from chromosome 6)
Jean-Loup Huret
56
AF9 (ALL1 fused gene from chromosome 9)
Jean-Loup Huret
58
AML1 (acute myeloid leukemia 1)
Jean-Loup Huret
59
E2A (E2A immunoglobulin enhancer-binding factor E12/E47)
Jean-Loup Huret
62
EEN (extra eleven nineteen leukemia fusion gene)
Jean-Loup Huret
64
ELL (eleven nineteen lysin rich leukemia gene)
Jean-Loup Huret
65
ENL (eleven nineteen leukemia)
Jean-Loup Huret
66
MLF1 (myelodysplasia/myeloid leukemia factor 1)
Jean-Loup Huret
67
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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MLL (myeloid/lymphoid or mixed lineage leukemia)
Jean-Loup Huret
68
NPM1 (nucleophosmin)
Jean-Loup Huret
70
Leukaemia Section
inv(3)(q21q26)
t(3;3)(q21;q26)
ins(3;3)(q26;q21q26)
Jean-Loup Huret
72
Plasma cell leukemia (PCL)
Lucienne Michaux
74
t(1;19)(q23;p13)
Jean-Loup Huret
76
t(8;16)(p11;p13)
Christine Pérot, Jean-Loup Huret
79
t(12;22)(p13;q11-12)
Jacqueline Van den Akker, Jean-Loup Huret
81
T-cell prolymphocytic leukemia (T-PLL)
Lucienne Michaux
83
inv(16)(p13q22)
t(16;16)(p13;q22)
del(16)(q22)
Jean-Loup Huret
85
t(6;11)(q27;q23)
Jean-Loup Huret
87
Chronic myelogenous leukaemia (CML)
Jean-Loup Huret
89
t(2;5)(p23;q35)
Jean-Loup Huret
92
t(4;11)(q21;q23)
Jean-Loup Huret
94
t(9;11)(p22;q23)
Jean-Loup Huret
96
t(9;22)(q34;q11) in CML
Jean-Loup Huret
98
t(10;11)(p12;q23)
Jean-Loup Huret
101
t(11;19)(q23;p13.1)
Jean-Loup Huret
102
t(11;19)(q23;p13.3)
Jean-Loup Huret
104
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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Gene Section
Mini Review
ABL (v-abl Abelson murine leukemia viral
oncogene homolog 1)
Jean-Loup Huret
Genetics, Department of Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021
Poitiers, France
Published in Atlas Database: October 1997
Online version is available at: http://AtlasGeneticsOncology.org/Genes/ABL.html
DOI: 10.4267/2042/32041
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology
(where can bind the binding protein BP1, to inhibit
SH1 activation) and SH2 (with high affinity towards
BCR first exon) -- domain 2: SH1 (with a selfphosphorylable tyrosine) -- domain 3: nuclear
localization domain (DNA binding, but not during
mitosis) -- domain 4: actin binding (cytoskeleton) -COOH-term; note: 1b (but not the 1a alternative)
myristylable allowing anchorage to the membrane.
Identity
Other names: ABL1
Location: 9q34.1
Local order: CAN is more telomeric, TAN1 even
more in 9q34.3.
DNA/RNA
Expression
Description
Ubiquitously expressed.
12 exons; 230 kb.
Localisation
Transcription
Mainly nuclear (tyrosine kinases are
cytoplasmic); can migrate into the cytoplasm.
Alternate splicing: 1a and 1b are 5’ alternative exons;
mRNA of 6 and 7 kb (with 1a and 1b respectively),
giving rise to 2 proteins of 145 kDa.
usually
Function
Protein
Inhibits cell growth through a direct interaction with Rb
in the nucleus.
Description
Homology
1130-1143 amino acids; 4 domains: of which are SH
(SRC homology) domains; NH2-term -- domain 1: SH3
SRC homology; like SRC, ABL is one of the tyrosine
kinases which are not membrane receptors.
DNA diagram
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
40
ABL (v-abl Abelson murine leukemia viral oncogene homolog 1)
Huret JL
Protein diagram
Hybrid/Mutated Gene
BCR/ABL the crucial event lies on der(22), id est 5’
BCR - 3’ ABL hybrid gene is the crucial one, while
ABL/BCR may or may not be expressed; breakpoint in
ABL is variable over a region of 200 kb, often between
the two alternative exons 1b and 1a, sometimes 5’ of 1b
or 3’ of 1a, but always 5’ of exon 2; breakpoint in BCR
is either:
1- in a region called M-bcr (for major breakpoint
cluster region), a cluster of 5.8 kb, between exons 12
and 16, also called b1 to b5 of M-bcr; most breakpoints
being either between b2 and b3, or between b3 and b4;
transcript is 8.5 kb long; this results in a 210 kDa
chimeric protein (P210); this is found in (most cases of)
CML, and in half cases of ALL or ANLL;
2- in a 35 kb region between exons 1 and 2, called mbcr (minor breakpoint cluster region), -> 7 kb mRNA,
resulting in a 190 kDa protein (P190); this is found in
half of the cases of ALL or ANLL.
Abnormal Protein
BCR/ABL P210 comprises the first 902 or 927 amino
acids from BCR, P190 only the 427 N-term from BCR;
BCR/ABL has a cytoplasmic localization, in contrast
with ABL, mostly nuclear.
Oncogenesis
That BCR/ABL has a cytoplasmic localization may
have a carcinogenetic role. The hybrid protein has an
increased protein kinase activity compared to ABL:
3BP1 (binding protein) binds normal ABL on SH3
domain, which prevents SH1 activation; with
BCR/ABL, the first (N-terminal) exon of BCR binds to
SH2, hidding SH3 which, as a consequence, cannot be
bound to 3BP1; thereof, SH1 is activated. Oncogenesis:
1-proliferation is induced through activation by
BCR/ABL of RAS signal transduction pathway, PI3-K
(phosphatidyl inositol 3’ kinase) pathway, and MYC;
2-BCR/ABL inhibits apoptosis;
3-BCR/ABL provokes cell adhesive abnormalities.
Implicated in
t(9;12)(q34;p12)/ALL → ETV6/ABL
Disease
Common ALL; yet poorly known.
Hybrid/Mutated Gene
5’ ETV6/TEL from 12p12 - 3’ ABL from 9q34.
Abnormal Protein
NH2-term Helix Loop Helix from ETV6(TEL) fused to
Tyr kinase from ABL COOH-term; localised in the
cytoskeleton.
Oncogenesis
Forms HLH-dependent oligomers, which may be
critical for Tyr kinase activation; oncogenesis may be
comparable to that induced by BCR/ABL.
t(9;22)(q34;q11)/CML → BCR/ABL
Disease
All CML have a t(9;22), at least at the molecular level
(BCR/ABL); phenotype and stem cell origin:
multipotent progenitor: t(9;22) is found in all myeloid
and B-lineage progenitors.
Prognosis
Median survival ≥ 4 yrs; alphaIFN therapy or BMT are
indicated.
Cytogenetics
Anomalies additional to the t(9;22) may be found either
at diagnosis or during course of the disease, or at the
time of acute transformation; mainly: +der(22), +8,
i(17q), +19, +21, -Y, -7, -17, +17; variant
translocations: t(9;22;V) and apparent t(V;22) or
t(9;V), where V is a variable chromosome, karyotypes
with apparently normal chromosomes 9 and 22, may be
found.
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
41
ABL (v-abl Abelson murine leukemia viral oncogene homolog 1)
Huret JL
Probe 1132H12 on a case of CML with t(9/22). Note the splitting of the probe, evident also on interphase nuclei.
Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics.
Prognosis
Is very poor.
Cytogenetics
The chromosome anomaly t(9;22) disappear during
remission, in contrast with BC-CML cases (CML in
blast crisis); additional anomalies: similar to what is
found in CML.
Hybrid/Mutated Gene
See above.
Abnormal Protein
See above.
Oncogenesis
See above.
t(9;22)(q34;q11)/ALL → BCR/ABL
Disease
Most often CD10+ ALL; frequent CNS involvement.
Prognosis
Is very poor (BMT is indicated); the breakpoint in Mbcr or in m-bcr (see below) does not seem to have
impact on prognosis.
Cytogenetics
The chromosome anomaly t(9;22) disappears during
remission, in contrast with BC-CML cases (CML in
blast crisis); additional anomalies: +der(22), -7, del(7q)
most often, +8, but not an i(17q), in contrast with CML
and ANLL cases; complex karyotypes, often
hyperploid; variants and complex translocations may be
found as in CML.
Hybrid/Mutated Gene
See above.
Abnormal Protein
See above.
Oncogenesis
See above.
References
Heiterkamp N, Groffen J. Molecular insights into the
Philadelphia translocation. Hematol Pathol 1991;5:1-10.
Kurzrock R, Talpaz M. The molecular pathology of chronic
myelogenous leukemia. Br J Haematol 1991;79 Suppl 1:34-37.
Gotoh A, Broxmeyer HE. The function of BCR/ABL and related
proto-oncogenes. Curr Opin Hematol 1997;4:3-11.
This article should be referenced as such:
t(9;22)(q34;q11)/ANLL → BCR/ABL
Huret JL. ABL (v-abl Abelson murine leukemia viral oncogene
homolog
1).
Atlas
Genet
Cytogenet
Oncol
Haematol.1997;1(2):40-42.
Disease
ANLL mostly M1 or M2 ANL.
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
42
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Mini Review
BCR (breakpoint cluster region)
Jean-Loup Huret
Genetics, Department of Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021
Poitiers, France
Published in Atlas Database: October 1997
Online version is available at: http://AtlasGeneticsOncology.org/Genes/BCR.html
DOI: 10.4267/2042/32042
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Localisation
Identity
Cytoplasmic.
Other names: BCR1, PHL
Location: 22q11.2
Local order: Distal to IGL in 22q11.1, proximal to
EWS, NF2, both in 22q12.
Function
Protein (serine/threonine) kinase; probable signal
transduction activity.
Homology
DNA/RNA
Drosophila rotund protein; other guanine-nucleotide
releasing factors of the CDC24 family.
Description
About 23 exons; 130 kb; 5’ centromere - 3’ telomere
orientation.
Implicated in
Transcription
t(9;22)(q34;q11)/CML → BCR/ABL
Into various mRNA, of which are 4.5 kb and 7 kb.
Disease
All CML have a t(9;22), at least at the molecular level
(BCR/ABL); phenotype and stem cell origin:
multipotent progenitor: t(9;22) is found in all myeloid
and B-lineage progenitors.
Prognosis
Median survival ≥ 4 yrs; alphaIFN therapy or BMT are
indicated.
Cytogenetics
Anomalies additional to the t(9;22) may be found either
at diagnosis or during course of the disease, or at the
Protein
Description
130 kDa, 190 kDa; mainly 160 kDa (1271 amino
acids); N-term ATP binding/Serine-Threonine kinase
domain, SH2 binding, GTP/GDP exchange domain,
and C-term domain which functions as a GTPase
activating protein for p21rac.
Expression
Ubiquitously expressed.
1
2 3 4 5 6 7 8 9 10 11
12 13 14 15 16
also called: b1 b2 b3 b4 b5
m-bcr:
t(9;22)->P190
M-bcr:
t(9;22)->P210
DNA diagram
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
43
17 18 19 20 21 22 23
BCR (breakpoint cluster region)
Huret JL
72M14 on a case of CML with t(9/22). Note that the probe remains on der(22)(Ph)
Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics
SH2, hidding SH3 which, as a consequence, cannot be
bound to 3BP1; thereof, SH1 is activated. Oncogenesis:
1-proliferation is induced through activation by
BCR/ABL of RAS signal transduction pathway, PI3-K
(phosphatidyl inositol 3’ kinase) pathway, and MYC;
2-BCR/ABL inhibits apoptosis;
3-BCR/ABL provokes cell adhesive abnormalities.
time of acute transformation; mainly: +der(22), +8,
i(17q), +19, +21, -Y, -7, -17, +17; variant
translocations: t(9;22;V) and apparent t(V;22) or
t(9;V), where V is a variable chromosome, karyotypes
with apparently normal chromosomes 9 and 22, may be
found.
Hybrid/Mutated Gene
BCR/ABL the crucial event lies on der(22), id est 5’
BCR - 3’ ABL hybrid gene is the crucial one, while
ABL/BCR may or may not be expressed; breakpoint in
ABL is variable over a region of 200 kb, often between
the two alternative exons 1b and 1a, sometimes 5’ of 1b
or 3’ of 1a, but always 5’ of exon 2; breakpoint in BCR
is either:
1- in a region called M-bcr (for major breakpoint
cluster region), a cluster of 5.8 kb, between exons 12
and 16, also called b1 to b5 of M-bcr; most breakpoints
being either between b2 and b3, or between b3 and b4;
transcript is 8.5 kb long; this results in a 210 kDa
chimeric protein (P210); this is found in (most cases of)
CML, and in half cases of ALL or ANLL;
2- in a 35 kb region between exons 1 and 2, called mbcr (minor breakpoint cluster region), -> 7 kb mRNA,
resulting in a 190 kDa protein (P190); this is found in
half of the cases of ALL or ANLL.
Abnormal Protein
BCR/ABL P210 comprises the first 902 or 927 amino
acids from BCR, P190 only the 427 N-term from BCR;
BCR/ABL has a cytoplasmic localization, in contrast
with ABL, mostly nuclear.
Oncogenesis
That BCR/ABL has a cytoplasmic localization may
have a carcinogenetic role. The hybrid protein has an
increased protein kinase activity compared to ABL:
3BP1 (binding protein) binds normal ABL on SH3
domain, which prevents SH1 activation; with
BCR/ABL, the first (N-terminal) exon of BCR binds to
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
t(9;22)(q34;q11)/ALL → BCR/ABL
Disease
Most often CD10+ ALL; frequent CNS involvement.
Prognosis
Is very poor (BMT is indicated); the breakpoint in Mbcr or in m-bcr (see below) does not seem to have
impact on prognosis.
Cytogenetics
The chromosome anomaly t(9;22) disappear during
remission, in contrast with BC-CML cases (CML in
blast crisis); Additional anomalies: +der(22), -7,
del(7q) most often, +8, but not an i(17q), in contrast
with CML and ANLL cases; Complex karyotypes,
often hyperploid; variants and complex translocations
may be found as in CML.
Hybrid/Mutated Gene
See above.
Abnormal Protein
See above.
Oncogenesis
See above.
t(9;22)(q34;q11)/ANLL → BCR/ABL
Disease
ANLL mostly M1 or M2 ANL.
Prognosis
Is very poor.
44
BCR (breakpoint cluster region)
Huret JL
Cytogenetics
The chromosome anomaly t(9;22) disappear during
remission, in contrast with BC-CML cases (CML in
blast crisis); additional anomalies: similar to what is
found in CML.
Hybrid/Mutated Gene
See above.
Abnormal Protein
See above.
Oncogenesis
See above.
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
References
Kurzrock R, Talpaz M. The molecular pathology of chronic
myelogenous leukemia. Br J Haematol 1991 Oct;79 Suppl
1:34-7. (Review).
Heisterkamp N, Groffen J. Molecular insights into the
Philadelphia translocation. Hematol Pathol 1991;5(1):1-10.
(Review).
Gotoh A, Broxmeyer HE. The function of BCR/ABL and related
proto-oncogenes. Curr Opin Hematol 1997 Jan;4(1):3-11.
This article should be referenced as such:
Huret JL. BCR (breakpoint cluster region). Atlas Genet
Cytogenet Oncol Haematol.1997;1(2):43-45.
45
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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Gene Section
Mini Review
ETO (eigth twenty one)
Jean-Loup Huret
Genetics, Department of Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021
Poitiers, France
Published in Atlas Database: October 1997
Online version is available at: http://AtlasGeneticsOncology.org/Genes/ETO.html
DOI: 10.4267/2042/32043
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Expression
Identity
Mainly in the brain; not in hematopoietic cells
(debated).
Other names: MTG8; CDR (cyclin D related gene);
AML1T1 (AML1 translocated to, 1); CBFA2T1
(CBFA2 translocated to, 1)
Location: 8q22
Localisation
Nuclear (probable).
Function
Putative transcription factor.
Homology
99% identical to the murine homolog.
Implicated in
ETO (8q22) in normal cells: clone dJ1155L8 - Courtesy
Mariano Rocchi, Resources for Molecular Cytogenetics.
Laboratories willing to validate the probes are welcome:
contact M Rocchi.
t(8;21)(q24;q22)/ANLL → AML1/ETO
Disease
ANLL, M2 mostly.
Prognosis
CR is obtained; median survival (1.5-2 yrs) is the range
with other ANLL or relatively better.
Cytogenetics
Additional anomalies are frequent: loss of Y or X
chromosome, del(7q)/-7, +8, del(9q); complex
t(8;21;Var) are known and have revealed that the
crucial event lies on der(8); in agreement with the fact
that both genes are transcribed from telomere to
centromere.
Hybrid/Mutated Gene
5’ AML1 - 3’ ETO.
Abnormal Protein
N-term AML1 with the Runt domain fused to the
nearly entire ETO.
Oncogenesis
The fusion protein retains the ability to recognize the
AML1 concensus binding site (→ negative dominant
competitor with the normal AML1) and to dimerize
DNA/RNA
Transcription
From telomere to centromere; alternate slicing at the 5’
end → MTG8A and MTG8B.
Protein
Protein Diagram
Description
577 or 604 amino acids (MTG8A and MTG8B
respectively), with a different N-term; 3 proline rich
domains (as in transcription factors), 2 of which being
also serine and threonine rich (as phosphorylation sites)
and 2 Zn fingers (cys.cys/cys.cys and cys.cys/his.cys),
a PEST region at the C terminus (conferring rapid
intracellular degradation).
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
46
ETO (eigth twenty one)
Huret JL
with the cbtb/CBTB subunit → probable altered
transcriptional regulation of normal AML1 target
genes.
Nucifora G, Rowley JD. AML1 and the 8;21 and 3;21
translocations in acute and chronic myeloid leukemia. Blood
1995 Jul 1;86(1):1-14. (Review).
References
This article should be referenced as such:
Huret JL. ETO (eigth twenty one). Atlas Genet Cytogenet
Oncol Haematol.1997;1(2):46-47.
Ohki M. Molecular basis of the t(8;21) translocation in acute
myeloid leukemia. Semin Cancer Biol 1993 Dec;4(6):369-75.
(Review).
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
47
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Short Communication
MN1 (meningioma 1)
Jean-Loup Huret
Genetics, Department of Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021
Poitiers, France
Published in Atlas Database: October 1997
Online version is available at: http://AtlasGeneticsOncology.org/Genes/MN1.html
DOI: 10.4267/2042/32044
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Prognosis
Yet uncertain; median survival 2 yrs.
Cytogenetics
Additional anomalies: +8.
Hybrid/Mutated Gene
5’ MN1 - 3’ ETV6.
Abnormal Protein
N-term MN1 and most of it, comprising the
glutamine/proline rich domain, fused to the DNA
binding of ETV6 in C-term; nuclear protein.
Oncogenesis
May act as an altered transcription factor.
Identity
Location: 22q11-12
DNA/RNA
Description
2 exons at least, the first being very CG rich and with
CAG repeats; spans about 70 kb.
Transcription
Alternate splicing: 4.5 and 8 kb mRNA; coding
sequence: 4.0 kb.
Protein
Meningioma (some of them)
Description
References
1319 and 1342 amino acids; glutamine and prolin rich
(may function as transactivation domains).
Buijs A, Sherr S, van Baal S, van Bezouw S, van der Plas D,
Geurts van Kessel A, Riegman P, Lekanne Deprez R,
Zwarthoff E, Hagemeijer A, et al. Translocation
(12;22)(p13;q11) in myeloproliferative disorders results in
fusion of the ETS-like TEL gene on 12p13 to the MN1 gene on
22q11. Oncogene 1995 Apr 20;10(8):1511-9. Erratum in
Oncogene 1995 Aug 17;11(4):809.
Expression
Ubiquitously expressed; high expression in muscle, low
otherwise.
Function
Lekanne Deprez RH, Riegman PH, Groen NA, Warringa UL,
van Biezen NA, Molijn AC, Bootsma D, de Jong PJ, Menon
AG, Kley NA, et al. Cloning and characterization of MN1, a
gene from chromosome 22q11, which is disrupted by a
balanced translocation in a meningioma. Oncogene 1995 Apr
20;10(8):1521-8.
Transcriptional regulator.
Implicated in
t(12;22)(p13;q11)/myeloid malignancies
→ MN1/ETV6
This article should be referenced as such:
Huret JL. MN1 (meningioma 1). Atlas Genet Cytogenet Oncol
Haematol.1997;1(2):48.
Disease
M4 ANLL and other myeloid malignancies (MDS...).
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
48
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Mini Review
PBX1 (pre-B-cell leukemia homeobox 1)
Jean-Loup Huret
Genetics, Department of Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021
Poitiers, France
Published in Atlas Database: November 1997
Online version is available at: http://AtlasGeneticsOncology.org/Genes/PBX1.html
DOI: 10.4267/2042/32045
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Other names: PRL
Location: 1q23
C-PBX1 at 1q23 in normal cells: PAC 953E11 - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics. Laboratories willing to
validate the probes are welcome: Contact M Rocchi.
DNA/RNA
Homology
Transcription
PBX2 and PBX3 have nearly identical homeodomains;
homeobox proteins; homologs of the fly protein
‘extradenticle’.
1.8 kb; alternate splicing → PBX1a and PBX1b,
different only in the C-term.
Implicated in
Protein
t(1;19)(q23;p13)/B-ALL → E2A/PBX1
Description
Disease
Pre B ALL mainly; CD19+, CD10+, CD9+.
Prognosis
Controversial data; associated with poor prognostic
features.
Cytogenetics
Two different forms: the balanced t(1;19); the
unbalanced form, with 2 normal chromosomes 1, a
der(19), and a normal chromosome 19: → partial
trisomy for 1q23-1qter and monosomy for 19p13.3pter; additional anomalies: in half of the cases; they are
various.
338 (PBX1b) and 430 (PBX1a) amino acids; 37 kDa;
homeodomain (to binds to DNA).
Expression
Ubiquitously expressed, except in B and T lineages.
Localisation
Nuclear (probable).
Function
Associated to HOX proteins, can bind to specific DNA
sequences (5’ ATCAATCAA 3’), for transcription
regulation.
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
49
PBX1 (pre-B-cell leukemia homeobox 1)
Huret JL
Mellentin JD, Nourse J, Hunger SP, Smith SD, Cleary ML.
Molecular analysis of the t(1;19) breakpoint cluster region in
pre-B
cell
acute
lymphoblastic
leukemias.
Genes
Chromosomes Cancer 1990 Sep;2(3):239-47.
Hybrid/Mutated Gene
5’ E2A from 19p13 fused to 3’ PBX1; breakpoints are
clustered on both genes.
Abnormal Protein
N-term transcriptional activation domains from E2A
fused to the Hox cooperative motif and homeodomain
of C-term PBX1.
Oncogenesis
Potent
transcriptional
activator;
pleiotropic
transforming activity.
Nourse J, Mellentin JD, Galili N, Wilkinson J, Stanbridge E,
Smith SD, Cleary ML. Chromosomal translocation t(1;19)
results in synthesis of a homeobox fusion mRNA that codes for
a potential chimeric transcription factor. Cell 1990 Feb
23;60(4):535-45.
Hunger SP. Chromosomal translocations involving the E2A
gene in acute lymphoblastic leukemia: clinical features and
molecular pathogenesis. Blood 1996 Feb 15;87(4):1211-24.
This article should be referenced as such:
References
Huret JL. PBX1 (pre-B-cell leukemia homeobox 1). Atlas Genet
Cytogenet Oncol Haematol.1997;1(2):49-50.
Kamps MP, Murre C, Sun XH, Baltimore D. A new homeobox
gene contributes the DNA binding domain of the t(1;19)
translocation protein in pre-B ALL. Cell 1990 Feb 23;60(4):54755.
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
50
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Short Communication
AF10 (ALL1 fused gene from chromosome 10)
Jean-Loup Huret
Genetics, Department of Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021
Poitiers, France
Published in Atlas Database: December 1997
Online version is available at: http://AtlasGeneticsOncology.org/Genes/AF10.html
DOI: 10.4267/2042/32046
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Localisation
Identity
Nuclear.
Location: 10p12
Function
Transcription factor.
Homology
Homology with AF17 and BR140.
Implicated in
t(10;11)(p12;q23)/ANLL → MLL/AF10
Disease
Mainly M4/M5 ANLL.
Cytogenetics
High diversity of reported breakpoints (from 10p11 to
10p15), and frequent additional inv(11): complexity of
the translocation.
Hybrid/Mutated Gene
5’ MLL - 3’ AF10; breakpoints are at variable places
along AF10.
Abnormal Protein
N-term AT hook and DNA methyltransferase from
MLL fused to the leucine zipper C-term of AF10.
AF10 (10p12) - Courtesy Mariano Rocchi, Resources for
Molecular Cytogenetics. Laboratories willing to validate the
probes are welcome: contact [email protected].
DNA/RNA
Transcription
inv ins (10;11)(p12;q23q12)/ANLL →
MLL-AF10
5’ telomeric → 3’ centromeric direction; 5.5 kb
mRNA; coding sequence: 3.1 kb.
Disease
Poorly known M4/M5 ANLL.
Hybrid/Mutated Gene
5’ MLL - 3’ AF10 and 5’ AF10 - 3’ HEAB, a gene
sitting in 11q12.
Abnormal Protein
Only MLL-AF10 is expressed.
Protein
Description
1027 amino acids; 109 kDa; N-term -- 3 Zn fingers -Glu/Lys rich domain -- Leucine zipper -- Poly Ser -- Cterm.
Expression
Mainly in the testis.
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
51
AF10 (ALL1 fused gene from chromosome 10)
Huret JL
t(10;11)(p13;q14-21) → CALM/AF10
and/or AF10-CALM
References
Bernard OA and Berger R. Molecular basis of 11q23
rearrangements in hematopoietic malignant proliferations.
Genes Chromosomes Cancer 1995 Jun;13(2):75-85.
Disease
Yet to be well delineated; T-cell ALL.
Prognosis
Uncertain (median survival 2 yrs?).
Cytogenetics
May well be confused
with the above
t(10;11)(p12;q23).
Hybrid/Mutated Gene
5’ CALM - 3’ AF10 and 5’ AF10 - 3’ CALM.
Abnormal Protein
Both CALM-AF10 and the reciprocal AF10-CALM are
expressed.
Chaplin T, Bernard O, Beverloo HB, Saha V, Hagemeijer A,
Berger R, Young BD. The t(10;11) translocation in acute
myeloid leukemia (M5) consistently fuses the leucine zipper
motif of AF10 onto the HRX gene. Blood 1995 Sep
15;86(6):2073-2076.
Dreyling MH, Martinez-Climent JA, Zheng M, Mao J, Rowley
JD, Bohlander SK. The t(10;11)(p13;q14) in the U937 cell line
results in the fusion of the AF10 gene and CALM, encoding a
new member of the AP-3 clathrin assembly protein family. Proc
Natl Acad Sci USA 1996 May 14;93(10):4804-4809.
Rubnitz JE, Behm FG, Downing JR. 11q23 rearrangements in
acute leukemia. Leukemia 1996 Jan;10(1):74-82. (Review).
Young BD and Saha V. Chromosome abnormalities in
leukemia: the 11q23 paradigm. Cancer Surv 1996;28:225-245.
Kobayashi H, Hosoda F, Maseki N, Sakurai M, Imashuku S,
Ohki M, Kaneko Y. Hematologic malignancies with the
t(10;11)(p13;q21) have the same molecular event and a variety
of morphologic or immunologic phenotypes. Genes
Chromosomes Cancer 1997 Nov;20(3):253-259.
Breakpoints
Note: the breakpoint in the t(10;11)(p13;q14-21) is
more in 5’ of AF10.
This article should be referenced as such:
Huret JL. AF10 (ALL1 fused gene from chromosome 10). Atlas
Genet Cytogenet Oncol Haematol.1997;1(2):51-52.
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
52
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Short Communication
AF17 (ALL1 fused gene from chromosome 17)
Jean-Loup Huret
Genetics, Department of Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021
Poitiers, France
Published in Atlas Database: December 1997
Online version is available at: http://AtlasGeneticsOncology.org/Genes/AF17.html
DOI: 10.4267/2042/32047
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Implicated in
Other names: MLLT6 (myeloid/lymphoid leukemia
translocated to, 6)
Location: 17q21
Local order: proximal to RARA, also in 17q21; HLF
is even more distal in 17q22.
t(11;17)(q23;q21)/ANLL → MLL/AF17
Probe(s) - Courtesy Mariano Rocchi, Resources for Molecular
Cytogenetics.
Disease
ANLL and MDS.
Cytogenetics
Additional anomaly: +8.
Hybrid/Mutated Gene
5’ MLL - 3’ AF17.
Abnormal Protein
N-term AT hook and DNA methyltransferase from
MLL fused to the leucine zipper C-term of AF17.
DNA/RNA
References
Transcription
Prasad R, Leshkowitz D, Gu Y, Alder H, Nakamura T, Saito H,
Huebner K, Berger R, Croce CM, Canaani E. Leucine-zipper
dimerization motif encoded by the AF17 gene fused to ALL-1
(MLL) in acute leukemia. Proc Natl Acad Sci USA 1994 Aug
16;91(17):8107-8111.
7.5 and 5 kb mRNA; coding sequence: 3.3 kb.
Protein
Bernard OA and Berger R. Molecular basis of 11q23
rearrangements in hematopoietic malignant proliferations.
Genes Chromosomes Cancer 1995 Jun;13(2):75-85.
Description
1093 amino acids; N-term - 3 Zn fingers (LAP type)
and a leucine zipper - C-term; a leucine zipper is a
dimerization motif.
Young BD and Saha V. Chromosome abnormalities in
leukemia: the 11q23 paradigm. Cancer Surv 1996;28:225-245.
Rubnitz JE, Behm FG, Downing JR. 11q23 rearrangements in
acute leukemia. Leukemia 1996 Jan;10(1):74-82. (Review).
Localisation
Nuclear.
This article should be referenced as such:
Function
Huret JL. AF17 (ALL1 fused gene from chromosome 17). Atlas
Genet Cytogenet Oncol Haematol.1997;1(2):53.
Transcriptional regulation factor.
Homology
With AF10 and BR140, a gene sitting in 3p25.
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
53
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Short Communication
AF4 (ALL1 fused gene from chromosome 4)
Jean-Loup Huret
Genetics, Department of Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021
Poitiers, France
Published in Atlas Database: December 1997
Online version is available at: http://AtlasGeneticsOncology.org/Genes/AF4.html
DOI: 10.4267/2042/32048
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Expression
Identity
Widely expressed.
Other names: FEL, MLLT2 (myeloid/lymphoid
leukemia translocated to, 2)
Location: 4q21
Localisation
Nuclear.
Function
Transcription activator.
Homology
LAF4.
Implicated in
t(4;11)(q21;q23)/acute
MLL/AF4
→
Disease
Typically CD19+ B-ALL, biphenotypic AL, at times
ANLL (M4/M5); may be congenital; treatment related
leukaemia (secondary to epipodophyllotoxins).
Prognosis
Median survival < 1 yr.
Cytogenetics
Additional chromosome anomalies are found in ¼ of
cases of which is the i(7q).
Hybrid/Mutated Gene
5’ MLL - 3’ AF4; 12 kb.
Abnormal Protein
240 kDa protein with about 1400 amino acids from
NH2 MLL and 850 from COOH AF4 (variable
breakpoints); the reciprocal may or may not be
expressed.
MLLT2 (4q21) - Courtesy Mariano Rocchi, Resources for
Molecular Cytogenetics. Laboratories willing to validate the
probes are welcome: contact [email protected].
DNA/RNA
Transcription
Alternate splicing in 5’ → 10.5 and 12 kb; coding
sequences: 3.6 kb.
Protein
Description
References
NH2 - Nuclear Targeting Sequence - COOH
1210 amino acids; 140 kDa; contains many serine and
proline rich sequences, a nuclear targeting sequence
and a concensus sequence for ATP/GTP binding.
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
leukaemias
Gu Y, Nakamura T, Alder H, Prasad R, Canaani O, Cimino G,
Croce CM, Canaani E. The t(4;11) chromosome translocation
of human acute leukemias fuses the ALL-1 gene, related to
Drosophila trithorax, to the AF-4 gene. Cell 1992;71:701-708.
54
AF4 (ALL1 fused gene from chromosome 4)
Huret JL
Morrissey J, Tkachuk DC, Milatovich A, Francke U, Link M,
Cleary ML. A serine/proline-rich protein is fused to HRX in
t(4;11) acute leukemias. Blood 1993;81:1124-1131.
Young BD, Saha V. Chromosome abnormalities in leukemia:
the 11q23 paradigm. Cancer Surv 1996;28:225-245. (Review).
Bernard OA, Berger R. Molecular basis of 11q23
rearrangements in hematopoietic malignant proliferations.
Genes Chromosomes Cancer 1995;13:75-85. (Review).
This article should be referenced as such:
Huret JL. AF4 (ALL1 fused gene from chromosome 4). Atlas
Genet Cytogenet Oncol Haematol.1997;1(2):54-55.
Rubnitz JE, Behm FG, Downing JR. 11q23 rearrangements in
acute leukemia. Leukemia 1996 Jan;10(1):74-82. (Review).
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
55
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Short Communication
AF6 (ALL1 fused gene from chromosome 6)
Jean-Loup Huret
Genetics, Department of Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021
Poitiers, France
Published in Atlas Database: December 1997
Online version is available at: http://AtlasGeneticsOncology.org/Genes/AF6.html
DOI: 10.4267/2042/32049
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Expression
Identity
Widely expressed.
Other names: MLLT4 (myeloid/lymphoid leukemia
translocated to, 4)
Location: 6q27
Localisation
Cytoplasmic.
Function
May be involved in molecular transport system; signal
transduction.
Homology
cno (drosophila).
Implicated in
t(6;11)(q27;q23)/ANLL → MLL/AF6
Disease
M4/M5 ANLL mainly.
Prognosis
Poor.
Cytogenetics
May be overlooked; +8 is a frequent additional
chromosome anomaly.
Hybrid/Mutated Gene
5’ MLL - 3’ AF6.
Abnormal Protein
NH2-term MLL (with the AT hook and DNA binding
motifs) and most of AF6.
AF6 (6q27) - Courtesy Mariano Rocchi, Resources for
Molecular Cytogenetics. Laboratories willing to validate the
probes are welcome: contact [email protected].
DNA/RNA
Transcription
8 kb mRNA; coding sequence: 4.8 kb.
References
Protein
Bernard OA, Berger R. Molecular basis of 11q23
rearrangements in hematopoietic malignant proliferations.
Genes Chromosomes Cancer 1995;13:75-85. (Review).
Description
1612 amino acids; contains a GLGF motif, which may
have a role in membrane/cytoskeleton relations.
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
Prasad R, Gu Y, Alder H, Nakamura T, Canaani O, Saito H,
Huebner K, Gale RP, Nowell PC, Kuriyama K, et al. Cloning of
the ALL-1 fusion partner, the AF-6 gene, involved in acute
myeloid leukemias with the t(6;11) chromosome translocation.
Cancer Res 1993 Dec 1;53(23):5624-8.
56
AF6 (ALL1 fused gene from chromosome 6)
Huret JL
Rubnitz JE, Behm FG, Downing JR. 11q23 rearrangements in
acute leukemia. Leukemia 1996 Jan;10(1):74-82. (Review).
This article should be referenced as such:
Young BD, Saha V. Chromosome abnormalities in leukemia:
the 11q23 paradigm. Cancer Surv 1996;28:225-245. (Review).
Huret JL. AF6 (ALL1 fused gene from chromosome 6). Atlas
Genet Cytogenet Oncol Haematol.1997;1(2):56-57.
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
57
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Short Communication
AF9 (ALL1 fused gene from chromosome 9)
Jean-Loup Huret
Genetics, Department of Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021
Poitiers, France
Published in Atlas Database: December 1997
Online version is available at: http://AtlasGeneticsOncology.org/Genes/AF9.html
DOI: 10.4267/2042/32050
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Implicated in
Other names: LTG9; MLLT3 (myeloid/lymphoid
leukemia translocated to 3)
Location: 9p22
t(9;11)(p22;q23)/ANLL → MLL/AF9
Disease
M5/M4 de novo and therapy related ANLL.
Prognosis
The prognosis may not be as poor as in other 11q23
leukaemias in de novo cases; very poor prognosis in
secondary ANLL cases.
Cytogenetics
May be overlooked; often as a sole anomaly.
Hybrid/Mutated Gene
Variable breakpoints on both genes.
Abnormal Protein
N-term -- AT hook and DNA methyltransferase from
MLL fused to the 192 C-term amino acids from AF9
(as breakpoints are variable, this is only an exemple).
AF9 (9p22) - Courtesy Mariano Rocchi, Resources for
Molecular Cytogenetics. Laboratories willing to validate the
probes are welcome: contact [email protected].
References
DNA/RNA
Albain KS, Le Beau MM, Ullirsch R, Schumacher H. Implication
of prior treatment with drug combinations including inhibitors of
topoisomerase II in therapy-related monocytic leukemia with a
9;11 translocation. Genes Chromosomes Cancer 1990
May;2(1):53-8. (Review).
Transcription
5 kb mRNA; coding sequence: 1.7 kb.
Bernard OA, Berger R. Molecular basis of 11q23
rearrangements in hematopoietic malignant proliferations.
Genes Chromosomes Cancer 1995;13:75-85. (Review).
Protein
Description
Joh T, Kagami Y, Yamamoto K, Segawa T, Takizawa J,
Takahashi T, Ueda R, Seto M. Identification of MLL and
chimeric MLL gene products involved in 11q23 translocation
and possible mechanisms of leukemogenesis by MLL
truncation. Oncogene 1996 Nov 7;13(9):1945-53.
568 amino acids; 63 kDa; serine and proline rich in
many places; possesses a nuclear targeting sequence.
Localisation
Rubnitz JE, Behm FG, Downing JR. 11q23 rearrangements in
acute leukemia. Leukemia 1996 Jan;10(1):74-82. (Review).
Nuclear.
Function
Transcription activator.
Young BD, Saha V. Chromosome abnormalities in leukemia:
the 11q23 paradigm. Cancer Surv 1996;28:225-245. (Review).
Homology
This article should be referenced as such:
With ENL (human).
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
Huret JL. AF9 (ALL1 fused gene from chromosome 9). Atlas
Genet Cytogenet Oncol Haematol.1997;1(2):58.
58
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Mini Review
AML1 (acute myeloid leukemia 1)
Jean-Loup Huret
Genetics, Department of Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021
Poitiers, France
Published in Atlas Database: December 1997
Online version is available at: http://AtlasGeneticsOncology.org/Genes/AML1.html
DOI: 10.4267/2042/32051
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Protein
Other names: CBFA2 (core binding factor A2),
CBFa2, PEBPaB (polyomavirus enhancer binding
protein aB)
Location: 21q22.3
AML1
Runt
transactiv .
Description
250, 453 amino acids and other forms; forms
heterodimers with CBFB.
Expression
Widely expressed, including hematopoietic cells at
various
stages
of
differentiation:
role
in
haematopoiesis.
Localisation
Nuclear.
AML1 (21q22.3) in normal cells: clone dJ1107L6 - Courtesy
Mariano Rocchi, Resources for Molecular Cytogenetics.
Laboratories willing to validate the probes are welcome:
contact M Rocchi.
Function
Transcription
factor
(activator)
for
various
hematopoietic-specific genes: binds to the core site 5’
PyGPyGGTPy 3’ of a number of promotors and
enhancers, as in GM-CSF (granulocyte-macrophage
colony stimulating factor, CSF1R (colony stimulating
factor 1 receptor), TCRb sites (T cell antigen
receptors), and myeloid myeloperoxidase.
DNA/RNA
Description
The gene spans a region of more than 120 kb.
Transcription
Homology
Transcription is from telomere to centromere → the
fusion gene is located on the ‘other’ chromosome (e.g.
the der(8) of the t(8;21), the der(3) of the t(3;21)...);
alternate splicing → transcripts of 2, 3.3, …, 7.5 and 8
kb.
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
1- Runt (drosophila): nuclear DNA binding protein;
role in segmentation (embryology);
2- AML2 (also called: CBFA3, CBFa3, PEBPaC),
located in 1p35-36, expressed in B lineage (3 and 5 kb
RNA);
3- AML3: (also called: CBFA1, CBFa1, PEBPaA) in
6p21;
4- cbfa family (mouse)
59
AML1 (acute myeloid leukemia 1)
Huret JL
β
α
Py G Py G G T Py
CBFβ and CBFα association to bind on the DNA core site : Py -G-Py -G-G-T-Py
5
6
7
Runt
transactiv.
AML1
t(12;21)
t(8;21)
t(3;21)
t(3;21)
t(5;21)
t(17;21)
t(8;21;Var) are known and have revealed that the
crucial event lies on der(8); in agreement with the fact
that both genes are transcribed from telomere to
centromere.
Hybrid/Mutated Gene
5’ AML1 - 3’ ETO.
Abnormal Protein
N-term AML1 with the Runt domain fused to the
nearly entire ETO.
Oncogenesis
The fusion protein retain the ability to recognize the
AML1 concensus binding site (→ negative dominant
competitor with the normal AML1) and to dimerize
with the cbtb/CBTB subunit → probable altered
transcriptional regulation of normal AML1 target
genes.
Implicated in
t(1;21)(p36;q22)
t(3;21)(q26;q22)/myelodysplastic
syndrome (MDS) or ANLL → EVI1 or
EAP-MDS1/AML1
Note: translocation protein includes most of the gene,
from the second untranslated exon.
Disease
CML-BC of myeloid type; ANLL and MDS, often
therapy related (secondary to antitopoisomerase II).
Hybrid/Mutated Gene
5’ AML1 - 3’ EAP or MDS1 or EVI1.
Abnormal Protein
AML1/EVI1: N-term -- Runt -- zn finger -- zn finger -acidic -- C-term.
t(12;21)(p12;q22)/ALL → ETV6-AML1
t(5;21)(q13;q22)/myelodysplastic
syndrome (MDS)
Disease
B cell ALL (CD10+).
Prognosis
CR in all cases; prognosis seems good.
Cytogenetics
Often undetectable without FISH; additional
anomalies: frequent del(12)(p12) on the other allele.
Hybrid/Mutated Gene
5’ ETV6 - 3’ AML1 on the der(21).
Abnormal Protein
Helix loop helix of TEL fused to the nearly entire
AML1 protein; the other TEL allele is often deleted.
t(8;21)(q24;q22)/ALL and ANLL →
AML1/ETO
Disease
ANLL; M2 mostly.
Prognosis
CR is obtained; median survival (1.5-2 yrs) is the range
with other ANLL or relatively better.
Cytogenetics
Additional cytogenetics anomalies: loss of Y or X
chromosome, del(7q)/-7, +8, del(9q); complex
t(17;21)(q11;q22)/ANLL
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
60
AML1 (acute myeloid leukemia 1)
Huret JL
Romana SP, Poirel H, Leconiat M, Flexor MA, Mauchauffé M,
Jonveaux P, Macintyre EA, Berger R, Bernard OA. High
frequency of t(12;21) in childhood B-lineage acute
lymphoblastic leukemia. Blood 1995 Dec 1;86(11):4263-9.
References
Ohki M. Molecular basis of the t(8;21) translocation in acute
myeloid leukemia. Semin Cancer Biol 1993 Dec;4(6):369-75.
(Review).
This article should be referenced as such:
Nucifora G, Rowley JD. AML1 and the 8;21 and 3;21
translocations in acute and chronic myeloid leukemia. Blood
1995 Jul 1;86(1):1-14. (Review).
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
Huret JL. AML1 (acute myeloid leukemia 1). Atlas Genet
Cytogenet Oncol Haematol.1997;1(2):59-61.
61
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Mini Review
E2A (E2A immunoglobulin enhancer-binding
factor E12/E47)
Jean-Loup Huret
Genetics, Department of Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021
Poitiers, France
Published in Atlas Database: December 1997
Online version is available at: http://AtlasGeneticsOncology.org/Genes/E2A.html
DOI: 10.4267/2042/32052
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Other names: TCF3 (Trancription Factor 3); ITF1;
Immunoglobulin Enhancer Binding Factors E12/E47
Location: 19p13.3
Local order: Not far from ENL, also in 19p13.3;
LYL1 is in 19p13.2-p13.1, and ELL in 19p13.1.
TAD: transcriptional activation domain; bHLH: basic helix loop
helix.
Expression
Widely expressed.
DNA/RNA
Localisation
Nuclear.
Function
Transcription regulation; heterodimerizes with tissuespecific bHLH proteins; homodimers are only found so
far in B-lineage lymphocytes; essential for normal Bcell hematopoiesis.
Homology
c-E2A (19p13.3) in normal cells: PAC 1116F22 - Courtesy
Mariano Rocchi, Resources for Molecular Cytogenetics.
Laboratories willing to validate the probes are welcome:
contact M Rocchi.
With other proteins with a Helix-Loop-Helix
dimerization domain signature, MYC type (MYC
family, of which is C-MYC, LYL1, TAL1).
Description
Implicated in
17 exons; 15a and 15b alternative.
Transcription
t(1;19)(q23;p13)/B-ALL → hybrid gene:
E2A/PBX1
4.4kb mRNA; coding sequence: 2.0 kb; alternate
splicing → E12 and E47, having different bHLH
encoding exons (+ also E2-5).
Disease
Pre B ALL mainly; CD19+, CD10+, CD9+.
Prognosis
Controversial data; associated with poor prognostic
features.
Cytogenetics
Two different forms: - the balanced t(1;19); - the
unbalanced form, with 2 normal chromosomes 1, a
der(19), and a normal chromosome 19: → partial
trisomy for 1q23-1qter and monosomy for 19p13.3-
Protein
Description
This gene encodes E12 and E47, which are proteins
which bind specifically to the immunoglobulin k chain
enhancer kE2; 648-654 amino acids; 68 kDa; domains:
2 transcriptional activation domains (→ transcription
factor) in the NH2-terminal, and a basic helix-loophelix (bHLH) DNA binding site in the C-term.
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
62
E2A (E2A immunoglobulin enhancer-binding factor E12/E47)
Huret JL
pter; Additional anomalies: in half of the cases; they
are various.
Hybrid/Mutated Gene
5’ E2A from 19p13 fused to 3’ PBX1; breakpoints are
clustered on both genes.
Abnormal Protein
N-term transcriptional activation domains from E2A
fused to the Hox cooperative motif and homeodomain
of C-term PBX1.
Oncogenesis
Potent
transcriptional
activator;
pleiotropic
transforming activity.
Oncogenesis
E2A/HLF homodimers bind to promoter/enhancer
elements of downstream target genes.
Breakpoints
Note: Breakpoints:
1- in t(1;19): are located (and dispersed) in the intron
13, and remove the bHLH domain;
2- in t(17;19) type I: are so far located at a given
nucleotide in intron 13;
3- in t(17;19) type II: are located in intron 12.
t(17;19)(q22;p13)/B-ALL → hybrid gene:
E2A/HLF
Disease
Childhood B-ALL.
Prognosis
Poor prognosis is likely.
Hybrid/Mutated Gene
5’ E2A - 3’ HLF.
Abnormal Protein
N-term transcriptional activation domains from E2A
fused to the basic leucine zipper from HLF C-term.
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
References
Hunger SP. Chromosomal translocations involving the E2A
gene in acute lymphoblastic leukemia: clinical features and
molecular pathogenesis. Blood 1996 Feb 15;87(4):1211-24.
This article should be referenced as such:
Huret JL. E2A (E2A immunoglobulin enhancer-binding factor
E12/E47).
Atlas
Genet
Cytogenet
Oncol
Haematol.1997;1(2):62-63.
63
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Short Communication
EEN (extra eleven nineteen leukemia fusion gene)
Jean-Loup Huret
Genetics, Department of Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021
Poitiers, France
Published in Atlas Database: December 1997
Online version is available at: http://AtlasGeneticsOncology.org/Genes/EEN.html
DOI: 10.4267/2042/32053
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Implicated in
Location: 19p13
t(11;19)(q23;p13)/ANLL → MLL/EEN
DNA/RNA
Disease
Yet unknown (only one case).
Hybrid/Mutated Gene
5’ MLL - 3’ EEN; breakpoint at exon 6 of MLL.
Abnormal Protein
Includes the N-term of MLL (with the AT hook and
DNA binding motifs) and the major functional domain
of EEN.
Transcription
Multiple transcript sizes, from 1 kb to the major form
of 2.6 kb.
Protein
Description
368 amino acids; 46 kDa (major product); contains a
central alpha-helical region and a SH3 (SRC homology
3) domain in C-term.
References
So CW, Caldas C, Liu MM, Chen SJ, Huang QH, Gu LJ, Sham
MH, Wiedemann LM, Chan LC. EEN encodes for a member of
a new family of proteins containing an Src homology 3 domain
and is the third gene located on chromosome 19p13 that fuses
to MLL in human leukemia. Proc Natl Acad Sci U S A. 1997
Mar 18;94(6):2563-8.
Expression
Wide, especially in the pancreas.
Homology
GRB2.
This article should be referenced as such:
Huret JL. EEN (extra eleven nineteen leukemia fusion gene).
Atlas Genet Cytogenet Oncol Haematol.1997;1(2):64.
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
64
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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Gene Section
Short Communication
ELL (eleven nineteen lysin rich leukemia gene)
Jean-Loup Huret
Genetics, Department of Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021
Poitiers, France
Published in Atlas Database: December 1997
Online version is available at: http://AtlasGeneticsOncology.org/Genes/ELL.html
DOI: 10.4267/2042/32054
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Implicated in
Other names: MEN (myeloid eleven nineteen
translocation: WARNING: it has nothing to do with
MEN1 and MEN2); ELL-PEN
Location: 19p13.1
Local order: Proximal from LYL1 in 19p13.2-p13.1;
ENL and E2A are even more distal in 19p13.3.
t(11;19)(q23;p13.1)/ANLL → MLL/ELL
Disease
Mainly M4/M5; treatment related leukemia; all ages.
Prognosis
Very poor.
Cytogenetics
Detected with R banding.
Hybrid/Mutated Gene
5’ MLL - 3’ ELL.
Abnormal Protein
AT hook and DNA methyltransferase from MLL fused
to most of ELL.
Oncogenesis
Potential transcription factor.
DNA/RNA
Transcription
Alternate splicing; 4.4 and 2.8 kb mRNA; coding
sequence: 1.9 kb.
Protein
Description
621 amino acids; 68 kDa; contains a Lysin rich domain
(basic motif).
References
Expression
Thirman MJ, Levitan DA, Kobayashi H, Simon MC, Rowley JD.
Cloning of ELL, a gene that fuses to MLL in a
t(11;19)(q23;p13.1) in acute myeloid leukemia. Proc Natl Acad
Sci USA 1994 Dec 6;91(25):12110-4.
Wide; especially in leukocytes, muscle, testis, placenta.
Localisation
Nuclear, except the nucleolus.
Mitani K, Kanda Y, Ogawa S, Tanaka T, Inazawa J, Yazaki Y,
Hirai H. Cloning of several species of MLL/MEN chimeric
cDNAs in myeloid leukemia with t(11;19)(q23;p13.1)
translocation. Blood 1995 Apr 15;85(8):2017-24.
Function
RNA polymerase II elongation factor, by suppressing
transient pausings → transcription activator; may also
inhibit initiation; possible target of VHL (Von Hippel
Lindau) tumour suppressor gene.
Shilatifard A, Lane WS, Jackson KW, Conaway RC, Conaway
JW. An RNA polymerase II elongation factor encoded by the
human ELL gene. Science 1996 Mar 29;271(5257):1873-6.
Shilatifard A, Haque D, Conaway RC, Conaway JW. Structure
and function of RNA polymerase II elongation factor ELL.
Identification of two overlapping ELL functional domains that
govern its interaction with polymerase and the ternary
elongation complex. J Biol Chem 1997 Aug 29;272(35):2235563.
Homology
ELL2.
This article should be referenced as such:
Huret JL. ELL (eleven nineteen lysin rich leukemia gene). Atlas
Genet Cytogenet Oncol Haematol.1997;1(2):65.
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
65
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Short Communication
ENL (eleven nineteen leukemia)
Jean-Loup Huret
Genetics, Department of Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021
Poitiers, France
Published in Atlas Database: December 1997
Online version is available at: http://AtlasGeneticsOncology.org/Genes/ENL.html
DOI: 10.4267/2042/32055
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Prognosis
Very poor, except in rare T-cell cases.
Cytogenetics
Detected with G-banding.
Hybrid/Mutated Gene
5’ MLL - 3’ ENL.
Abnormal Protein
AT hook and DNA methyltransferase from MLL fused
to, most often, the nearly entire ENL.
Identity
Other names: ENL (eleven nineteen leukemia);
LTG19;
MLLT1
(myeloid/lymphoid
leukemia
translocated to, 1)
Location: 19p13.3
Local order: Not far from E2A, also in 19p13.3; LYL1
is in 19p13.2-p13.1 and ELL in 19p13.1.
DNA/RNA
Transcription
References
4.7 kb mRNA; coding sequence: 1.7 kb.
Tkachuk DC, Kohler S, Cleary ML. Involvement of a homolog
of Drosophila trithorax by 11q23 chromosomal translocations in
acute leukemias. Cell 1992 Nov 13;71(4):691-700.
Protein
Description
Bernard OA and Berger R. Molecular basis of 11q23
rearrangements in hematopoietic malignant proliferations.
Genes Chromosomes Cancer 1995 Jun;13(2):75-85.
559 amino acids; 62 kDa; serine/proline rich protein;
contains a nuclear targeting sequence and a consensus
sequence for ATP/GTP binding.
Wide.
Joh T, Kagami Y, Yamamoto K, Segawa T, Takizawa J,
Takahashi T, Ueda R, Seto M. Identification of MLL and
chimeric MLL gene products involved in 11q23 translocation
and possible mechanisms of leukemogenesis by MLL
truncation. Oncogene 1996 Nov 7;13(9):1945-53.
Localisation
Rubnitz JE, Behm FG, Downing JR. 11q23 rearrangements in
acute leukemia. Leukemia 1996 Jan;10(1):74-82. (Review).
Nuclear.
Young BD and Saha V. Chromosome abnormalities in
leukemia: the 11q23 paradigm. Cancer Surv 1996;28:225-245.
Expression
Function
Transcription activator.
Homology
With AF9.
This article should be referenced as such:
Huret JL. ENL (eleven nineteen leukemia). Atlas Genet
Cytogenet
Oncol
Haematol.1997;1(2):66
.
Implicated in
t(11;19)(q23;p13.3)/acute leukaemias →
MLL/ENL
Disease
ALL (CD19+), biphenotypic AL, ANLL (M4/M5);
mainly congenital; treatment related leukaemia.
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
66
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Short Communication
MLF1 (myelodysplasia/myeloid leukemia factor 1)
Jean-Loup Huret
Genetics, Department of Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021
Poitiers, France
Published in Atlas Database: December 1997
Online version is available at: http://AtlasGeneticsOncology.org/Genes/MLF1.html
DOI: 10.4267/2042/32056
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Implicated in
Location: 3q25
Local order: EVI1/MDS1 is more telomeric (in 3q26),
BCL6 even more in 3q27.
t(3;5)(q25;q34)/ANLL or MDS →
NPM1/MLF1
Disease
ANLL, MDS, BC-CML; trilineage involvement.
Prognosis
Very poor.
Cytogenetics
Location of breakpoints difficult to ascertain.
Hybrid/Mutated Gene
5’ NPM1 - 3’ MLF1 on der(5).
Abnormal Protein
Nuclear protein.
DNA/RNA
Transcription
Alternate splicing: 1.4 and 2.4 kb.
Protein
Description
267 amino acids; 31 kDa; does not contain known
functional motifs.
Expression
References
MLF1 transcripts widely expressed (gonads, muscle,
heart, kidney, and colon).
Yoneda-Kato N, Look AT, Kirstein MN, Valentine MB,
Raimondi SC, Cohen KJ, Carroll AJ, Morris SW. The
t(3;5)(q25.1;q34) of myelodysplastic syndrome and acute
myeloid leukemia produces a novel fusion gene, NPM-MLF1.
Oncogene 1996 Jan 18;12(2):265-75.
Localisation
Cytoplasmic localisation.
Homology
None is known, apart from MLF2 (40% homology).
This article should be referenced as such:
Huret JL. MLF1 (myelodysplasia/myeloid leukemia factor 1).
Atlas Genet Cytogenet Oncol Haematol.1997;1(2):67.
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
67
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Mini Review
MLL (myeloid/lymphoid or mixed lineage
leukemia)
Jean-Loup Huret
Genetics, Department of Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021
Poitiers, France
Published in Atlas Database: December 1997
Online version is available at: http://AtlasGeneticsOncology.org/Genes/MLL.html
DOI: 10.4267/2042/32057
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
segments of homology with trithorax, in particular in
the C-term.
Other names: ALL1, HRX, Htrx (human trithorax),
TRX1
Location: 11q23
Local order: telomeric to PLZF, centromeric from
RCK.
Expression
DNA/RNA
Nuclear.
Wide; especially in: brain, kidney, thyroid, lymphoid
tissue.
Localisation
Function
Transcriptional regulatory factor.
Homology
Trithorax (drosophila); G9a (human).
Implicated in
Note: 5 to 10 % of acute leukaemias (ALL, ANLL,
biphenotypic AL, treatment related leukemia, infant
leukemia) with poor prognosis.
t(1;11)(p32;q23)/ALL → MLL/AF1p
t(1;11)(q21;q23)/ANLL → MLL/AF1q
t(4;11)(q21;q23)/acute leukaemias →
MLL/AF4
MLL (11q23) - Courtesy Mariano Rocchi, Resources for
Molecular Cytogenetics. Laboratories willing to validate the
probes are welcome: contact [email protected].
Description
21 exons, spanning over 100 kb.
Transcription
Disease
Typically CD19+ B-ALL, biphenotypic AL, at times
ANLL (M4/M5); may be congenital; treatment related
leukaemia (secondary to epipodophyllotoxins).
Prognosis
Median survival < 1 yr.
Cytogenetics
Additional chromosome anomalies are found in ¼ of
cases of which is the i(7q).
In a centromeric to telomeric direction; 13 and 15 kb;
coding sequence: 11.9 kb.
Protein
Description
3969 amino acids; 431 kDa; contains two DNA binding
motifs: a AT hook (to bind to the minor grove), and
Zinc fingers to bind to the major grove of DNA, a
DNA methyl transferase motif, a bromodomain, and
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
68
MLL (myeloid/lymphoid or mixed lineage leukemia)
Huret JL
Hybrid/Mutated Gene
5’ MLL - 3’ AF4; 12 kb.
Abnormal Protein
240 kDa protein with about 1400 amino acids from
NH2-MLL and 850 from COOH-AF4 (variable
breakpoints); the reciprocal may or may not be
expressed.
Oncogenesis
Potential transcription factor.
t(11;19)(q23;p13.3)/acute leukaemias →
MLL/ENL
Disease
ALL (CD19+), biphenotypic AL, ANLL (M4/M5);
mainly congenital; treatment related leukaemia.
Prognosis
Very poor, except in rare T-cell cases.
Cytogenetics
Detected with G-banding.
Hybrid/Mutated Gene
5’ MLL - 3’ ENL.
Abnormal Protein
AT hook and DNA methyltransferase from MLL fused
to, most often, the nearly entire ENL.
t(6;11)(q27;q23)/ANLL → MLL/AF6
t(9;11)(p22;q23)/ANLL → MLL/AF9
Disease
M5/M4 de novo and therapy related ANLL.
Prognosis
The prognosis may not be as poor as in other 11q23
leukaemias in de novo cases; very poor prognosis in
secondary ANLL cases.
Cytogenetics
May be overlooked; often as a sole anomaly.
Hybrid/Mutated Gene
Variable breakpoints on both genes.
Abnormal Protein
N-term -- AT hook and DNA methyltransferase from
MLL fused to the 192 C-term amino acids from AF9
(as breakpoints are variable, this is only an exemple).
Trisomy 11/ANLL → MLL tandem
duplication
Other 11q23 rearrangements
Breakpoints
Note: spanning a 8 kb genomic region; between exons
5 to 11; highly variable on the partner, ranging from
close to the NH2-term in ENL, to near the COOH-term
in AF9.
t(10;11)(p12;q23)/ANLL → MLL/AF10
t(11;17)(q23;q21)/ANLL → MLL/AF17
t(11;19)(q23;p13.1)/ANLL → MLL/ELL
References
Disease
Mainly M4/M5; treatment related leukemia; all ages.
Prognosis
Very poor.
Cytogenetics
Detected with R-banding.
Hybrid/Mutated Gene
5’ MLL - 3’ ELL.
Abnormal Protein
AT hook and DNA methyltransferase from MLL fused
to most of ELL.
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
Bernard OA, Berger R. Molecular basis of 11q23
rearrangements in hematopoietic malignant proliferations.
Genes Chromosom Cancer 1995;13:75-85.
Schichman SA, Canaani E, Croce CM. Self-fusion of the ALL1
gene. A new genetic mechanism for acute leukemia. JAMA
1995;273:571-576.
Rubnitz JE, Behm FG, Downing JR. 11q23 rearrangements in
acute leukemia. Leukemia 1996 Jan;10(1):74-82. (Review).
Young BD, Saha V. Chromosome abnormalities in leukemia:
the 11q23 paradigm. Cancer Surv 1996;28:225-245.
This article should be referenced as such:
Huret JL. MLL (myeloid/lymphoid or mixed lineage leukemia).
Atlas Genet Cytogenet Oncol Haematol.1997;1(2):68-69.
69
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Short Communication
NPM1 (nucleophosmin)
Jean-Loup Huret
Genetics, Department of Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021
Poitiers, France
Published in Atlas Database: December 1997
Online version is available at: http://AtlasGeneticsOncology.org/Genes/NPM1.html
DOI: 10.4267/2042/32058
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Protein
Other names: NPM, B23, numatrin, NO38
Location: 5q34-35
Description
294 amino acids; contains a metal binding site,
domains rich in acidic amino acids, and a nuclear
localisation signal; forms homo-hexameres; binds to
single and double strand nucleic acids.
Localisation
Nuclear, mainly in the nucleolus.
Function
RNA binding nucleolar phosphoprotein that may
transport
ribonucleoproteins
between
cellular
compartments; may also have a role in DNA
replication.
NPM1 (5q35) - Courtesy Mariano Rocchi, Resources for
Molecular Cytogenetics. Laboratories willing to validate the
probes are welcome: contact [email protected].
Implicated in
t(2;5)(p23;q35)/CD30+ NHL →
NPM1/ALK
DNA/RNA
Disease
High grade NHL; most often: CD30+ anaplastic large
cell type.
Prognosis
Nonetheless, a 80% five yr survival may be associated
with this anomaly.
Cytogenetics
Additional anomalies are most often found.
Description
12 exons.
Transcription
In a centromeric → telomeric orientation; transcription
is cell-cycle regulated, reaching peaks at G1/S
transition and being baseline at S/G2; 1.6 kb mRNA.
Protein Diagram
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
70
NPM1 (nucleophosmin)
Huret JL
Hybrid/Mutated Gene
5’ NPM1-3’ ALK on der(5).
Abnormal Protein
680 amino acids; the 117 N-term amino acids of NPM1
are fused to the 563 C-term amino acids of ALK (i.e.
the entire cytoplasmic portion of ALK); no apparent
expression of the ALK/NPM1 counterpart; localisation:
both in the cytoplasm and in the nucleus.
Oncogenesis
Via the kinase function activated by oligomerization of
NPM1-ALK mediated by the NPM1 part.
Abnormal Protein
With the 117 N-term amino acids of NPM1.
Breakpoints
Note: within the 4th intron in the cases of t(2;5) or
t(5;17), within the 6th intron in case of t(3;5).
t(3;5)(q25;q34)/ANLL or MDS →
NPM/MLF1
References
Disease
ANLL, MDS, BC-CML; trilineage involvement.
Prognosis
Very poor.
Cytogenetics
Location of breakpoints difficult to ascertain.
Hybrid/Mutated Gene
5’ NPM-3’ MLF1 on der(5).
Abnormal Protein
With the 175 N-term amino acids of NPM1; nuclear
protein.
Morris SW, Kirstein MN, Valentine MB, Dittmer KG, Shapiro
DN, Saltman DL, Look AT. Fusion of a kinase gene, ALK, to a
nucleolar protein gene, NPM, in non-Hodgkin’s lymphoma.
Science 1994 Mar 4;263(5151):1281-4.
Redner RL, Rush EA, Faas S, Rudert WA, Corey SJ. The
t(5;17) variant of acute promyelocytic leukemia expresses a
nucleophosmin-retinoic
acid
receptor
fusion.
Blood
1996;87:882-886.
Yoneda-Kato N, Look AT, Kirstein MN, Valentine MB,
Raimondi SC, Cohen KJ, Carroll AJ, Morris SW. The
t(3;5)(q25.1;q34) of myelodysplastic syndrome and acute
myeloid leukemia produces a novel fusion gene, NPM-MLF1.
Oncogene 1996 Jan 18;12(2):265-75.
Bischof D, Pulford K, Mason DY, Morris SW. Role of the
nucleophosmin (NPM) portion of the non-Hodgkin’s lymphomaassociated NPM-anaplastic lymphoma kinase fusion protein in
oncogenesis. Mol Cell Biol 1997 Apr;17(4):2312-25.
t(5;17)(q34;q21)/M3-ANLL →
NPM1/RARa
Chan PK, Chan FY, Morris SW, Xie Z. Isolation and
characterization of the human nucleophosmin/B23 (NPM)
gene: identification of the YY1 binding site at the 5’ enhancer
region. Nucleic Acids Res 1997 Mar 15;25(6):1225-32.
Disease
Promyelocytic ANLL (M3-ANLL).
Cytogenetics
Variant translocation of the well known t(15;17).
Hybrid/Mutated Gene
5’ NPM1-3’ RARa on der(5).
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
This article should be referenced as such:
Huret JL. NPM1 (nucleophosmin). Atlas Genet Cytogenet
Oncol Haematol.1997;1(2):70-71.
71
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Mini Review
inv(3)(q21q26)
t(3;3)(q21;q26)
ins(3;3)(q26;q21q26)
Jean-Loup Huret
Genetics, Department of Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021
Poitiers, France
Published in Atlas Database: October 1997
Online version is available at: http://AtlasGeneticsOncology.org/Anomalies/inv3.html
DOI: 10.4267/2042/32059
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Note: the three chromosome anomalies are variants of each other, and they share identical features.
inv(3)(q21q26) G-banding (top) - Courtesy Diane H. Norback, Eric B. Johnson, Sara Morrison-Delap Cytogenetics at the Waisman
Center (left and middle) and Jean-Luc Lai and Alain Vanderhaegen, bottom: t(3;3)(q21;q26) (bottom) G-banding (left) - Courtesy Diane
H. Norback, Eric B. Johnson, Sara Morrison-Delap (left and center left), Jean-Luc Lai and Alain Vanderhaegen (middle), and R-banding
(middle right and right) - Courtesy Christiane Charrin.
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
72
inv(3)(q21q26). t(3;3)(q21;q26). ins(3;3)(q26;q21q26)
Huret JL
RPN1 (ribophorin 1)
Clinics and pathology
Location: 3q21
Disease
Results of the chromosomal
anomaly
Acute non lymphocytic leukemia (ANLL), often
preceeded by myelodysplastic syndrome (MDS); MDS;
may occur as additional anomaly in chronic
myelogenous leukemia (CML) with t(9;22), with
thrombocytosis, often at the time of the blast crisis; has
also been found in other myeloproliferative disorders.
Phenotype / cell stem origin
ANLL of various subtypes (M1, M2, M4, M6, M7);
MDS: often RAEB; an early stem cell, prior to lineage
commitment, is implicated.
Epidemiology
1M/1F; median age is 50 yrs.
Clinics
Blood data: elevated or normal (instead of low)
platelets count; bone marrow: erythroid and
megakaryocytic dysplasia, with micromegakaryocytes
with hypolobulated nuclei.
Cytology
CD34+, CD13+, CD33+, DR+, but also, coexpression
of the T-cell characteristic CD7+, showing the
multilineage involvement.
Prognosis
Median survival (from 66 cases herein reviewed) is
only 4 mths.
Hybrid gene
Description
RPN1 enhancer juxtaposed to EVI1.
References
Jenkins RB, Tefferi A, Solberg LA Jr, Dewald GW. Acute
leukemia with abnormal thrombopoiesis and inversions of
chromosome 3. Cancer Genet Cytogenet 1989 Jun;39(2):16779.
Jotterand Bellomo M, Parlier V, Mühlematter D, Grob JP, Beris
P. Three new cases of chromosome 3 rearrangement in bands
q21 and q26 with abnormal thrombopoiesis bring further
evidence to the existence of a 3q21q26 syndrome. Cancer
Genet Cytogenet 1992 Apr;59(2):138-60. (Review).
Grigg AP, Gascoyne RD, Phillips GL, Horsman DE. Clinical,
haematological and cytogenetic features in 24 patients with
structural rearrangements of the Q arm of chromosome 3. Br J
Haematol 1993 Jan;83(1):158-65.
Fonatsch C, Gudat H, Lengfelder E, Wandt H, SillingEngelhardt G, Ludwig WD, Thiel E, Freund M, Bodenstein H,
Schwieder G, et al. Correlation of cytogenetic findings with
clinical features in 18 patients with inv(3)(q21q26) or
t(3;3)(q21;q26). Leukemia 1994 Aug;8(8):1318-26.
Secker-Walker LM, Mehta A, Bain B. Abnormalities of 3q21
and 3q26 in myeloid malignancy: a United Kingdom Cancer
Cytogenetic Group study. Br J Haematol 1995 Oct;91(2):490501.
Cytogenetics
Shi G, Weh HJ, Dührsen U, Zeller W, Hossfeld DK.
Chromosomal abnormality inv(3)(q21q26) associated with
multilineage hematopoietic progenitor cells in hematopoietic
malignancies. Cancer Genet Cytogenet 1997 Jul 1;96(1):5863.
Additional anomalies
- Alone or with -7 in 30% of cases each;
- nv(3) can be an additional anomaly to
t(9;22)(q34;q11)(20%), but, also, t(9;22) has been
found additional to inv(3) !
- del(5q)(10%).
This article should be referenced as such:
Huret JL. inv(3)(q21q26). t(3;3)(q21;q26).
ins(3;3)(q26;q21q26). Atlas Genet Cytogenet Oncol
Haematol.1997;1(2):72-73.
Genes involved and Proteins
EVI1
Location: 3q26
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
73
Atlas of Genetics and Cytogenetics
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Leukaemia Section
Mini Review
Plasma cell leukemia (PCL)
Lucienne Michaux
Department of Hematology and Center for Human Genetics, Cliniques Universitaires Saint Luc Avenue
Hippocrate 10 1200 Brussels, Belgium
Published in Atlas Database: October 1997
Online version is available at: http://AtlasGeneticsOncology.org/Anomalies/PlasmCel.html
DOI: 10.4267/2042/32060
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology
responses have been observed with melphalan and
prednisone; the response rate seems to be higher with
combination therapy than with single alkylating agents;
prognosis: the overall survival is short (few months).
Clinics and pathology
Disease
Plasma cell dyscrasia; called primary PCL when it is
diagnosed in the leukemic phase, and secondary PCL
when there is leukemic transformation of a previously
recognized multiple myeloma.
Phenotype / cell stem origin
Proliferation involving plasma cell expressing
cytoplasmic immunoglobulin, CD38, plasma cell
antigene 1; a minority of cells express CD10, HLA-DR,
and CD20; the nature of the clonogenic cell in multiple
myeloma is unknown; the presence of multiple
hematopoietic surface antigenes on malignant plasma
cells suggests its origin from a pluripotent stem cell.
Epidemiology
Rare disorder; approximately 60% of patients have the
primary form; affects patients of more than 40 years of
age; patients with primary PCL are younger than
patients with the secondary PCL; slightly more
frequent in men than in women.
Clinics
Patients with primary PCL have a greater incidence of
hepatosplenomegaly and lymphadenopathy, and fewer
lytic bone lesions.
Blood data: these data are similar to those of multiple
myeloma, except that there are circulating plasma cells;
patients with PCL have more than 20% plasma cells in
their peripheral blood and an absolute plasma cell count
equal or above 2000/mm3; additionnally, patients with
primary PCL have higher platelets counts and smaller
M components compared to patients with secondary
PCL.
Prognosis
Evolution: this disease is usually progressive;
secondary PCL rarely responds to chemotherapy
because patients already received alkylating agents and
became resistant to them; in the primary form,
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
Cytogenetics
Cytogenetics, morphological
Cytogenetic aberrations are detected more frequently in
PCL than in multiple myeloma; the percentage of
abnormal cases varies in different series but seems to
be more than 50%; the overall pattern of cytogenetic
changes is very similar to the pattern observed in
multiple myeloma; numerical changes and/or structural
aberrations have been described; in large series,
hyperdiploidy is observed in 61 to 68% of cases, where
as pseudodiploidy and hypodiploidy occur in 9 to 20
and 10 to 30% of patients, respectively; monosomy 13
and trisomy 9 are the most frequent numerical
abnormalities; hypodiploidy is more common in PCL
than in myeloma. Apart from chromosome 9, gains also
involve chromosomes 3, 5, 7, 11, 15, and 19, whereas
losses also involve chromosome X and Y; structural
aberrations mainly involve chromosome 14, with 14q+
resulting from translocation t(11;14)(q13;q32) or other
changes (e.g. Burkitt’s translocations); chromosomes
16(p or q), 1(p or q), 19(p or q), 6q, 17q, 2p and 7q
might also be involved.
Cytogenetics, molecular
Chromosomal changes are detectable by conventional
cytogenetic techniques or by FISH; in addition,
comparative genomic hybridization showed to be a
useful tool in PCL, allowing assessment of regions
showing copy number changes.
Genes involved and Proteins
Note: Analysis of DNA content of plasma cells
demonstrates abnormalities in almost all patients; in
addition, rearrangements and amplification of the
74
Plasma cell leukemia (PCL)
Michaux L
including 117 patients at diagnosis. Blood 1995 May
1;85(9):2490-7. (Review).
proto-oncogene C-MYC have been reported, as well as
point mutations of NRAS and KRAS genes; molecular
rearrangements or point mutations of the tumour
suppressor genes RB1 and P53 have been reported; the
molecular
breakpoint
of
the
translocation
t(11;14)(q13;q32) involved the PRAD1 gene in 2 cases.
Meeus P, Stul MS, Mecucci C, Cassiman JJ, Van den Berghe
H. Molecular breakpoints of t(11;14)(q13;q32) in multiple
myeloma. Cancer Genet Cytogenet 1995 Aug;83(1):25-7.
Weh HJ, Bartl R, Seeger D, Selbach J, Kuse R, Hossfeld DK.
Correlations between karyotype and cytologic findings in
multiple myeloma. Leukemia 1995 Dec;9(12):2119-22.
References
Zandecki M, Laï JL, Facon T. Multiple myeloma: almost all
patients are cytogenetically abnormal. Br J Haematol 1996
Aug;94(2):217-27.
Dewald GW, Kyle RA, Hicks GA, Greipp PR. The clinical
significance of cytogenetic studies in 100 patients with multiple
myeloma, plasma cell leukemia, or amyloidosis. Blood 1985
Aug;66(2):380-90.
Avet-Loiseau H, Andree-Ashley LE, Moore D 2nd, Mellerin MP,
Feusner J, Bataille R, Pallavicini MG. Molecular cytogenetic
abnormalities in multiple myeloma and plasma cell leukemia
measured using comparative genomic hybridization. Genes
Chromosomes Cancer 1997 Jun;19(2):124-33.
Durie BG. Cellular and molecular genetic features of myeloma
and related disorders. Hematol Oncol Clin North Am 1992
Apr;6(2):463-77.
Calasanz MJ, Cigudosa JC, Odero MD, Ferreira C, Ardanaz
MT, Fraile A, Carrasco JL, Solé F, Cuesta B, Gullon A.
Cytogenetic analysis of 280 patients with multiple myeloma
and related disorders:primary breakpoints and clinical
correlations. Genes Chromosomes Cancer 1997 Feb;18(2):8493.
Jonveaux P, Berger R. Chromosome studies in plasma cell
leukemia and multiple myeloma in transformation. Genes
Chromosomes Cancer 1992 Jun;4(4):321-5.
Corradini P, Inghirami G, Astolfi M, Ladetto M, Voena C,
Ballerini P, Gu W, Nilsson K, Knowles DM, Boccadoro M, et al.
Inactivation of tumor suppressor genes, p53 and Rb1, in
plasma cell dyscrasias. Leukemia 1994 May;8(5):758-67.
This article should be referenced as such:
Laï JL, Zandecki M, Mary JY, Bernardi F, Izydorczyk V, Flactif
M, Morel P, Jouet JP, Bauters F, Facon T. Improved
cytogenetics in multiple myeloma: a study of 151 patients
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
Michaux L. Plasma cell leukemia (PCL). Atlas Genet
Cytogenet Oncol Haematol.1997;1(2):74-75.
75
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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Leukaemia Section
Mini Review
t(1;19)(q23;p13)
Jean-Loup Huret
Genetics, Department of Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021
Poitiers, France
Published in Atlas Database: October 1997
Online version is available at: http://AtlasGeneticsOncology.org/Anomalies/t0119.html
DOI: 10.4267/2042/32061
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Note: balanced form: -1, -19, +der(1), +der(19); unbalanced form: -19, +der(19).
Balanced t(1;19)(q23;p13)(top left) and der(19) t(1;19)(q23;p13) G-banding (bottom left) - Courtesy Jean-Luc Lai; and R-banding (right)
top: - Editor, below: - Courtesy Christiane Charrin.
the most frequent ALL in childhood); 3 male/4 female
patients.
Clinics
Moderate organomegaly; frequent CNS involvement;
blood data: high WBC (median 20 X 109/l); high LDH.
Cytology
CD19+, CD10+, and also CD9+.
Prognosis
Chromosome anomaly associated with adverse
prognostic features; CR in most cases; median event
Clinics and pathology
Disease
ALL, L1/L2 type; exceptionally found in L3-like ALL,
T-ALL, NHL, or ANLL.
Phenotype / cell stem origin
‘Pre B’ (cIg+) ALL; may be cIg- or sIg+.
Epidemiology
5% of ALL, or 20% of pre B ALL; found in children
and young adults (1-60 yrs, median: 10 yrs → one of
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
76
t(1;19)(q23;p13)
Huret JL
free survival: 2 yrs; no age (?) or blood data prognostic
significance; according to some -but not other- authors,
the unbalanced form is of better prognosis (5 yr
survival = 70%); median survival: 4 yrs in children, 6
mths in adults in one study, > 3yrs in adults in another.
Protein
Contains transcriptional activation domains and a basic
helix-loop-helix DNA binding site; binds specifically to
an immunoglobulin enhancer; nuclear localisation;
transcription factor.
Cytogenetics
Results of the chromosomal
anomaly
Cytogenetics, morphological
Breakpoint is in 19p13.3; two different forms (with
different prognoses?): - the balanced t(1;19), one fourth
of cases, with a der(1) and a der(19); - the unbalanced
form, found in ¾ cases, with 2 normal chromosomes 1,
a der(19), and 1 normal chromosome 19: → partial
trisomy for 1q23-1qter and monosomy for 19p13.3pter; the 2 forms can be in mosaic; note: 19p13 and
19q13 may be confused (e.g. literature reports).
Hybrid gene
Description
5’ E2A from 19p13 fused to 3’ PBX1; breakpoints are
clustered on both genes (between exons 13 and 14 in
E2A); the reciprocal 5’ PBX1 - 3’ E2A is not
transcribed.
Fusion protein
Additional anomalies
In half cases; partial dup(1q), +6, del(6q), +8, i(9q),
+17, i(17q), +21, t(17;19)(q22;p13) is not stricto sensu
a variant, but, so far, an equivalent, with HLF (hepatic
leukemia factor), on 17q22, involved in the
translocation.
Description
550 amino acids; 85 kDa; N-term transcriptional
activation domains from E2A fused to the Hox
cooperative motif and homeodomain of C-term PBX1;
potent transcriptional activator.
Expression localisation
Nuclear localisation.
Oncogenesis
Pleiotropic transforming activity.
Genes involved and Proteins
Note: the following are (most often) involved, except
in some cases lacking the cIg expression:
PBX1
Location: 1q23
DNA / RNA
Alternate PBX1a and PBX1b.
Protein
Contains a homeodomain to binds to DNA; nuclear
localisation; transcription regulation.
References
Kamps MP, Murre C, Sun XH, Baltimore D. A new homeobox
gene contributes the DNA binding domain of the t(1;19)
translocation protein in pre-B ALL. Cell 1990 Feb 23;60(4):54755.
Mellentin JD, Nourse J, Hunger SP, Smith SD, Cleary ML.
Molecular analysis of the t(1;19) breakpoint cluster region in
pre-B
cell
acute
lymphoblastic
leukemias.
Genes
Chromosomes Cancer 1990 Sep;2(3):239-47.
Nourse J, Mellentin JD, Galili N, Wilkinson J, Stanbridge E,
Smith SD, Cleary ML. Chromosomal translocation t(1;19)
results in synthesis of a homeobox fusion mRNA that codes for
a potential chimeric transcription factor. Cell 1990 Feb
23;60(4):535-45.
Monica K, Galili N, Nourse J, Saltman D, Cleary ML. PBX2 and
PBX3, new homeobox genes with extensive homology to the
human proto-oncogene PBX1. Mol Cell Biol 1991
Dec;11(12):6149-57.
Secker-Walker LM, Berger R, Fenaux P, Lai JL, Nelken B,
Garson M, Michael PM, Hagemeijer A, Harrison CJ, Kaneko Y,
et al. Prognostic significance of the balanced t(1;19) and
unbalanced
der(19)t(1;19)
translocations
in
acute
lymphoblastic leukemia. Leukemia 1992 May;6(5):363-9.
c-PBX1 at 1q23 in normal cells: PAC 1146N1 - Courtesy
Mariano Rocchi, Resources for Molecular Cytogenetics.
Laboratories willing to validate the probes are welcome:
contact M Rocchi.
Lu Q, Wright DD, Kamps MP. Fusion with E2A converts the
Pbx1 homeodomain protein into a constitutive transcriptional
activator in human leukemias carrying the t(1;19) translocation.
Mol Cell Biol 1994 Jun;14(6):3938-48.
E2A
Location: 19p13
DNA / RNA
Alternate splicing → E12 and E47.
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
Pui CH, Raimondi SC, Hancock ML, Rivera GK, Ribeiro RC,
Mahmoud HH, Sandlund JT, Crist WM, Behm FG.
Immunologic, cytogenetic, and clinical characterization of
childhood acute lymphoblastic leukemia with the t(1;19)(q23;
p13) or its derivative. J Clin Oncol 1994 Dec;12(12):2601-6.
77
t(1;19)(q23;p13)
Huret JL
Troussard X, Rimokh R, Valensi F, Leboeuf D, Fenneteau O,
Guitard AM, Manel AM, Schillinger F, Leglise C, Brizard A, et
al. Heterogeneity of t(1;19)(q23;p13) acute leukemias. French
Haematological Cytology Group. Br J Haematol 1995
Mar;89(3):516-26.
This article should be referenced as such:
Huret JL. t(1;19)(q23;p13). Atlas Genet Cytogenet Oncol
Haematol.1997;1(2):76-78.
Hunger SP. Chromosomal translocations involving the E2A
gene in acute lymphoblastic leukemia: clinical features and
molecular pathogenesis. Blood 1996 Feb 15;87(4):1211-24.
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
78
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Short Communication
t(8;16)(p11;p13)
Christine Pérot, Jean-Loup Huret
Laboratoire de Cytogenetique, Hopital Saint-Antoine, Paris, France (CP);
Genetics, Department of Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021
Poitiers, France (JLH)
Published in Atlas Database: October 1997
Online version is available at: http://AtlasGeneticsOncology.org/Anomalies/t0816.html
DOI: 10.4267/2042/32062
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Clinics and pathology
Genes involved and Proteins
Disease
MOZ
ANLL; t-ANLL
Phenotype / cell stem origin
M4, M5a, M5b; possible involvement of a granulomonocytic precursor; no preceeding MDS.
Epidemiology
Rare disease (<1% of ANLL); found in children
(including infants) and young adults of both sexes.
Clinics
Disseminated intra vascular coagulation may be
present; extramedullary infiltration; 20% of the cases
could be therapy-related.
Cytology
Erythrophagocytosis, strong peroxidase and esterase
activities.
Prognosis
Poor: remission may be obtained in half cases;
infections, bleeding; survival is often less than 1 year.
Location: 8p11
Cytogenetics
References
Additional anomalies
Brizard A, Guilhot F, Huret JL, Benz-Lemoine E, Tanzer J. The
8p11 anomaly in ‘monoblastic’ leukemia. Leuk Res
1988;12(8):693-7.
CBP
Location: 16p13
Results of the chromosomal
anomaly
Hybrid gene
Description
5’ MOZ - 3’ CBP
Fusion protein
Description
N-term MOZ fused to most of CBP; 3722 amino acids;
415 kDa; combines the MOZ finger motifs (DNA
binding) and acetyl transferase with the transcriptional
coactivator from CBP; the reciprocal CBP-MOZ has no
role (as it is out of frame).
In half cases; +8, various; complex karyotype may be
found.
Quesnel B, Kantarjian H, Bjergaard JP, Brault P, Estey E, Lai
JL, Tilly H, Stoppa AM, Archimbaud E, Harousseau JL, et al.
Therapy-related acute myeloid leukemia with t(8;21), inv(16),
and t(8;16): a report on 25 cases and review of the literature. J
Clin Oncol 1993 Dec;11(12):2370-9. (Review).
Variants
Complex t(8;16;Var) involving a (variable) third
chromosome have been described; 8p11 breakpoint
with another partner as well, of which is the recurrent
t(8;22)(p11;q13), which may involve P300 on 22q13 in
the place of CBP: this translocation would therefore be
an equivalent (not identical), and not a simple variant
with hidden 16p13 involvement.
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
Borrow J, Stanton VP Jr, Andresen JM, Becher R, Behm FG,
Chaganti RS, Civin CI, Disteche C, Dube I, Frischauf AM,
Horsman D, Mitelman F, Volinia S, Watmore AE, Housman
DE. The translocation t(8;16)(p11;p13) of acute myeloid
leukemia fuses a putative acetyltransferase to the CREBbinding protein. Nat Genet 1996 Sep;14(1):33-41.
79
t(8;16)(p11;p13)
Pérot C, Huret JL
Velloso ER, Mecucci C, Michaux L, Van Orshoven A, Stul M,
Boogaerts M, Bosly A, Cassiman JJ, Van Den Berghe H.
Translocation t(8;16)(p11;p13) in acute non-lymphocytic
leukemia: report on two new cases and review of the literature.
Leuk Lymphoma 1996 Mar;21(1-2):137-42. (Review).
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
This article should be referenced as such:
Pérot C, Huret JL. t(8;16)(p11;p13). Atlas Genet Cytogenet
Oncol Haematol.1997;1(2):79-80.
80
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Mini Review
t(12;22)(p13;q11-12)
Jacqueline Van den Akker, Jean-Loup Huret
Laboratoire De Cytogenetique, Hôpital Saint-Antoine, 184 rue du Faubourg Saint-Antoine, 75571 Paris,
Cedex 12, France (JVDA);
Genetics, Department of Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021
Poitiers, France (JLH)
Published in Atlas Database: October 1997
Online version is available at: http://AtlasGeneticsOncology.org/Anomalies/t1222.html
DOI: 10.4267/2042/32063
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
G- banding - Courtesy Melanie Zenger and Claudia Haferlach.
Clinics and pathology
Genes involved and Proteins
Disease
ETV6
Myeloid lineage (ANLL, MDS)
Phenotype / cell stem origin
M4 ANLL often (6/11); M7 ANLL, other ANLL;
RAEB evolving towards ANLL; ‘atypical CML’; may
occur secondary to genotoxic exposure.
Epidemiology
Yet poorly known; median age: 22 yrs (range 8-60;
n=11 cases herein reviewed); male predominance so far
(8/3).
Prognosis
Yet uncertain: survival range 0 mths - 6 yrs, median 2
yrs, n=9.
Location: 12p13
DNA / RNA
9 exons; alternate splicing.
Protein
Contains a Helix-Loop-Helix and ETS DNA binding
domains; wide expression; nuclear localisation; ETSrelated transcription factor.
MN1
Location: 22q11
DNA / RNA
Alternate splicing.
Protein
Glutamine and prolin rich protein; widely expressed;
transcriptional regulator.
Cytogenetics
Results of the chromosomal
anomaly
Cytogenetics, morphological
Easily detected, especially with R-banding.
Additional anomalies
Hybrid gene
+8 in half cases; various (e.g. del(5q)); sole anomaly in
3/11.
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
Description
Variable breakpoints in ETV6.
81
t(12;22)(p13;q11-12)
Van den Akker J, Huret JL
Fusion protein
References
Description
N term- MN1-ETV6 -C term, with most of MN1,
including the glutamine/proline rich domain, fused to
the DNA binding of ETV6; the reciprocal ETV6/MN1
may or may not be expressed.
Expression localisation
Nuclear protein.
Oncogenesis
May act as an altered transcription factor.
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
Buijs A, Sherr S, van Baal S, van Bezouw S, van der Plas D,
Geurts van Kessel A, Riegman P, Lekanne Deprez R,
Zwarthoff E, Hagemeijer A, et al. Translocation
(12;22)(p13;q11) in myeloproliferative disorders results in
fusion of the ETS-like TEL gene on 12p13 to the MN1 gene on
22q11. Oncogene 1995 Apr 20;10(8):1511-9.
This article should be referenced as such:
Van den Akker J, Huret JL. t(12;22)(p13;q11-12). Atlas Genet
Cytogenet Oncol Haematol.1997;1(2):81-82.
82
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Mini Review
T-cell prolymphocytic leukemia (T-PLL)
Lucienne Michaux
Department of Hematology and Center for Human Genetics, Cliniques Universitaires Saint Luc Avenue
Hippocrate 10 1200 Brussels, Belgium
Published in Atlas Database: October 1997
Online version is available at: http://AtlasGeneticsOncology.org/Anomalies/TPLL.html
DOI: 10.4267/2042/32064
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology
inv(14)(q11q32)
or
as
a
translocation
t(14;14)(q11;q32); another reported change involving
14q11 is a translocation t(X;14)(q28;q11), similar to
the translocation observed in ataxia-telangectasia,
involving the Mature T-cell Prolymphocyte 1 (MTCP1)
gene located at Xq28.
-Other recurrent changes involve chromosome 8 either
as i(8)(q10) or as der(8) t(8;8).
-Finally, some aberrations involving 12p have been
reported.
Clinics and pathology
Disease
Chronic T-cell lymphoproliferative syndrome
Phenotype / cell stem origin
Disease affecting mature T-cells.
T-cell prolymphocytes usually express CD3, CD5 and
CD7; they have either a T-helper (CD4+/CD8-) or a Tsuppressor (CD4-/CD8+) phenotype; a small number of
cases may co-express CD4 and CD8; this finding is
more prevalent in the small cell variant of T-PLL than
in classic T-PLL.
Epidemiology
Very rare disease; represents 20% of prolymphocytic
leukemias; the disease occurs at advanced age,
typically in the 7th or 8th decade; slight male
predominance.
Clinics
Splenomegaly is common; lymphadenopathy at
presentation is unusual but more frequent than in BPLL; blood data: high leucocyte counts usually
exceeding 100x109/l; T-cell prolymphocytes have the
same
morphologic
features
than
B-cell
prolymphocytes; a small cell variant of T-PLL has been
described.
Prognosis
Evolution: progresses rapidly and is generally more
aggressive than B-PLL; prognosis: poor response to
chemotherapy is observed; median survival is
approximatively 7 months from diagnosis.
Genes involved and Proteins
Note: as with other T-cell neoplasms, T-PLL exhibits
clonal rearrangement of T-cell receptor genes;
translocation t(X;14)(q28;q11) may result into fusion of
MTCP1 with TCRa-d genes; finally, the TCL1 locus on
chromosome 14q32 might also been involved; biallelic
mutation in ATM can occur.
References
Brito-Babapulle V, Pittman S, Melo JV, Pomfret M, Catovsky D.
Cytogenetic studies on prolymphocytic leukemia. 1. B-cell
prolymphocytic leukemia. Hematol Pathol 1987;1(1):27-33.
Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA,
Gralnick HR Sultan C. Proposals for the classification of
chronic (mature) B and T lymphoid leukemias. FrenchAmerican-British (FAB) Cooperative Group. J Clin Pathol 1989
Jun;42(6):567-84.
Matutes E, Brito-Babapulle V, Swansbury J, Ellis J, Morilla R,
Dearden C, Sempere A, Catovsky D. Clinical and laboratory
features of 78 cases of T-prolymphocytic leukemia. Blood 1991
Dec 15;78(12):3269-74.
Fisch P, Forster A, Sherrington PD, Dyer MJ, Rabbitts TH. The
chromosomal translocation t(X;14)(q28;q11) in T-cell prolymphocytic leukemia breaks within one gene and activates
another. Oncogene 1993 Dec;8(12):3271-6.
Cytogenetics
Stern MH, Soulier J, Rosenzwajg M, Nakahara K, Canki-Klain
N, Aurias A, Sigaux F, Kirsch IR. MTCP-1: a novel gene on the
human chromosome Xq28 translocated to the T cell receptor
alpha/delta locus in mature T cell proliferation. Oncogene 1993
Sep;8(9):2475-83.
Cytogenetics, morphological
Few cases have been reported in the literature so far;
karyotypes are usually complex.
-14q11 abnormalities: very frequent, either as an
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
83
T-cell prolymphocytic leukemia (T-PLL)
Michaux L
Virgilio L, Isobe M, Narducci MG, Carotenuto P, Camerini B,
Kurosawa N, Abbas-ar-Rushdi, Croce CM, Russo G.
Chromosome walking on the TCL1 locus involved in T-cell
neoplasia. Proc Natl Acad Sci USA 1993 Oct 15;90(20):92759.
as a basis for distinguishing low-grade and high-grade
lymphomas. Blood 1994 Jan 15;83(2):505-11.
Thick J, Mak YF, Metcalfe J, Beatty D, Taylor AM. A gene on
chromosome Xq28 associated with T-cell prolymphocytic
leukemia in two patients with ataxia telangiectasia. Leukemia
1994 Apr;8(4):564-73.
Heinonen K, Mahlamäki E, Hämäläinen E, Nousiainen T,
Mononen I. Multiple karyotypic abnormalities in three cases of
small cell variant of T-cell prolymphocytic leukemia. Cancer
Genet Cytogenet 1994 Nov;78(1):28-35.
Madani A, Choukroun V, Soulier J, Cacheux V, Claisse JF,
Valensi F, Daliphard S, Cazin B, Levy V, Leblond V, Daniel
MT, Sigaux F, Stern MH. Expression of p13MTCP1 is
restricted to mature T-cell proliferations with t(X;14)
translocations. Blood 1996 Mar 1;87(5):1923-7.
Mossafa H, Brizard A, Huret JL, Brizard F, Lessard M, Guilhot
F, Tanzer J. Trisomy 8q due to i(8q) or der(8) t(8;8) is a
frequent lesion i T-prolymphocytic leukemia: four new cases
and a review of the literature. Br J Haematol 1994 Apr;86:780785.
This article should be referenced as such:
Michaux L. T-cell prolymphocytic leukemia (T-PLL). Atlas
Genet Cytogenet Oncol Haematol.1997;1(2):83-84.
Schlegelberger B, Himmler A, Gödde E, Grote W, Feller AC,
Lennert K. Cytogenetic findings in peripheral T-cell lymphomas
.
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
84
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Short Communication
inv(16)(p13q22)
t(16;16)(p13;q22)
del(16)(q22)
Jean-Loup Huret
Genetics, Department of Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021
Poitiers, France
Published in Atlas Database: November 1997
Online version is available at: http://AtlasGeneticsOncology.org/Anomalies/inv16.html
DOI: 10.4267/2042/32065
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Additional anomalies
None in 2/3 of cases; +8, +22 in 15% each, del(7q),
+21.
Variants
Are known:
1- t(16;16)(p13;q22); - del(16)(q22): may be associated
with less typical phenotype and preceding MDS, older
age, complex karyotype, worse prognosis;
2- but also: translocations of 16q22 with: 1p31-32,
3q21, 5q33, associated with eosinophils anomalies.
Identity
Note: the three chromosome anomalies are variants of
each other, and they share identical clinical features.
Clinics and pathology
Disease
ANLL/MDS
Phenotype / cell stem origin
Nearly pathognomonic of M4eo: M4 with marked
eosinophilia; rarely: M2 or M5, M4 without eo, MDS;
known cases of BC-CML with M4eo phenotype and
inv(16). CD2 (T-cell marker) may be co-expressed.
Epidemiology
5% of ANLL, 20% of M4.
Clinics
CNS involvement is frequent, according to some
authors.
Cytology
Most often: eosinophils > 5%, with large immature
basophilic granules, NASCA+, in the bone marrow (but
normal in blood: this M4 do not show the ‘eo’
characteristic in blood).
Prognosis
High CR rate; better prognosis than most other ANLL;
median survival may be 5 yrs.
Genes involved and Proteins
MYH11
Location: 16p13
Protein
Contains a N-term ATPase head responsible for actin
binding and mechanical movement, and a C-term long
repeat of coil-coil domain to facilitate filament
aggregates; member of the myosin II family.
CBFb
Location: 16q22
Protein
Subunit of the transcription factor complex CBF; CBFb
by itself does not contain any DNA binding motif or
transcriptional activation domain, but forms a dimer
with CBFa: → transcription factor.
Cytogenetics
Results of the chromosomal
anomaly
Cytogenetics, morphological
Hybrid gene
May be overlooked, especially with R-banding; best
seen without banding procedure (‘giemsa’) for some
workers.
Description
Breakpoint in CBFB intron 5.
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
85
inv(16)(p13q22). t(16;16)(p13;q22). del(16)(q22)
Huret JL
abnormality: a
Oct;3(10):740-5.
Transcript
No reciprocal MYH11-CBFB.
Detection protocole
RT-PCR.
of
18
cases.
Leukemia
1989
Campbell LJ, Challis J, Fok T, Garson OM. Chromosome 16
abnormalities associated with myeloid malignancies. Genes
Chromosomes Cancer 1991 Jan;3(1):55-61.
Betts DR, Rohatiner AZ, Evans ML, Rassam SM, Lister TA,
Gibbons B. Abnormalities of chromosome 16q in myeloid
malignancy: 14 new cases and a review of the literature.
Leukemia 1992 Dec;6(12):1250-6. (Review).
Fusion protein
Description
N-term -the first 165 (or 133 in a few cases) amino
acids of CBFb, removing only 17 or 22 amino acids to
the tail of MYH11- C-term; also variable breakpoint in
MYH11; identical in the cases of RAEBT and BCCML.
Expression localisation
Localized in the nucleus.
Liu PP, Hajra A, Wijmenga C, Collins FS. Molecular
pathogenesis of the chromosome 16 inversion in the M4Eo
subtype of acute myeloid leukemia. Blood 1995 May
1;85(9):2289-302. (Review).
Shurtleff SA, Meyers S, Hiebert SW, Raimondi SC, Head DR,
Willman CL, Wolman S, Slovak ML, Carroll AJ, Behm F, et al.
Heterogeneity in CBF beta/MYH11 fusion messages encoded
by the inv(16)(p13q22) and the t(16;16)(p13;q22) in acute
myelogenous leukemia. Blood 1995 Jun 15;85(12):3695-703.
References
This article should be referenced as such:
Huret JL. inv(16)(p13q22). t(16;16)(p13;q22). del(16)(q22).
Atlas Genet Cytogenet Oncol Haematol.1997;1(2):85-86.
Bernard P, Dachary D, Reiffers J, Marit G, Wen Z, Jonveaux P,
David B, Lacombe F,Broustet A. Acute nonlymphocytic
leukemia with marrow eosinophilia and chromosome 16
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
report
86
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Mini Review
t(6;11)(q27;q23)
Jean-Loup Huret
Genetics, Department of Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021
Poitiers, France
Published in Atlas Database: November 1997
Online version is available at: http://AtlasGeneticsOncology.org/Anomalies/t0611.html
DOI: 10.4267/2042/32066
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
t(6;11)(q27;q23) G-banding - Courtesy Diane H. Norback, Eric B. Johnson, Sara Morrison-Delap Cytogenetics at the Waisman Center
(top and middle), and Jean-Luc Lai (below).
Epidemiology
Still poorly known; found in children and young adults;
male predominance.
Clinics
Frequent infections; organomegaly; blood data:
moderate WBC.
Clinics and pathology
Disease
ANLL
Phenotype / cell stem origin
M4, M5 mostly; T-cell ALL at times; therapy related
AL.
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
87
t(6;11)(q27;q23)
Huret JL
hook and Zinc fingers), and a DNA methyl transferase
motif; wide expression; nuclear localisation;
transcriptional regulatory factor.
Treatment
BMT is indicated.
Prognosis
Very poor (as in other 11q23 rearrangements); rare
remission; short survival.
Results of the chromosomal
anomaly
Cytogenetics
Hybrid gene
Cytogenetics, morphological
Description
5’ MLL - 3’ AF6
May be missinterpreted as a del(11q), as chromosome 6
involvement may be overlooked.
Fusion protein
Cytogenetics, molecular
Description
About 1400 NH2-term amino acids (with the AT hook
and DNA binding motifs) from MLL and most of AF6,
starting at amino acid 26.
Therefore, FISH may be needed.
Additional anomalies
Are present in most cases; +8 in particular; +3; +19;
+21.
References
Genes involved and Proteins
Prasad R, Gu Y, Alder H, Nakamura T, Canaani O, Saito H,
Huebner K, Gale RP, Nowell PC, Kuriyama K, et al. Cloning of
the ALL-1 fusion partner, the AF-6 gene, involved inacute
myeloid leukemias with the t(6;11) chromosome translocation.
Cancer Res 1993 Dec 1;53(23):5624-8.
AF6
Location: 6q27
Protein
Contains a GLGF motif; widely expressed; cytoplasmic
localisation; role in signal transduction.
Welborn JL, Jenks HM, Hagemeijer A. Unique clinical features
and prognostic significance of the translocation (6;11) in acute
leukemia. Cancer Genet Cytogenet 1993 Feb;65(2):125-9.
(Review).
MLL
This article should be referenced as such:
Location: 11q23
Protein
431 kDa; contains two DNA binding motifs (a AT
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
Huret JL. t(6;11)(q27;q23). Atlas Genet Cytogenet Oncol
Haematol.1997;1(2):87-88.
.
88
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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Leukaemia Section
Mini Review
Chronic myelogenous leukaemia
(CML)
Jean-Loup Huret
Genetics, Department of Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021
Poitiers, France
Published in Atlas Database: December 1997
Online version is available at: http://AtlasGeneticsOncology.org/Anomalies/CML.html
DOI: 10.4267/2042/32067
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Clinics and pathology
Disease
CML is a chronic myeloproliferative syndrome.
Phenotype / cell stem origin
Multipotent (and primitive: CD34+, DR-) progenitor:
t(9;22) is found in any myeloid progenitor and in Blymphocytes progenitors, but, most often, not in the Tcells.
Epidemiology
Annual incidence: 10/106 (from 1/106 in childhood to
30/106 after 60 yrs); median age: 30-60 yrs; sex ratio:
1.2M/1F.
Clinics
Splenomegaly; chronic phase (lasts about 3 yrs) with
maintained cell’s normal activities, followed by
accelerated phase(s)(blasts still < 15%), and blast crisis
(BC-CML) with blast cells > 30%; blood data: WBC:
100 X 109/l and more during chronic phase, with
basophilia; a few blasts; thrombocytosis may be
present; low leucocyte alkaline phosphatases; typical
acute leukaemia (AL) blood data at the time of myeloid
or lymphoid-type blast crisis.
Cytology
Hyperplastic bone marrow; granulocytes proliferation,
with maturation; followed by typical AL cytology (see:
t(9;22)(q34;q11) in ALL, t(9;22)(q34;q11) in ANLL).
Treatment
AlphaIFN therapy or bone marrow transplantation
(BMT), donor leukocytes infusions.
Prognosis
Median survival: 4 yrs with conventional therapy
(hydroxyurea, busulfan), 6 yrs with alphaIFN therapy;
bone marrow transplantation may cure the patient;
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
q11
q12
q13
q3 4
9
22
otherwise, the best treatment to date associates
interferon alpha, hydroxyurea and cytarabine.
Cytogenetics
Cytogenetics, morphological
All CML have a t(9;22), at least at the molecular level
(see below); but not all t(9;22) are found in CML: this
translocation may also be seen in ALL, and in ANLL
(see: t(9;22)(q34;q11) in ALL, t(9;22)(q34;q11) in
ANLL), and the same genes are involved in the three
diseases; in CML, the chromosomal anomaly persists
during remission, in contrast with AL cases.
Cytogenetics, molecular
Is a useful tool for diagnostic ascertainment in the case
of a ‘masked Philadelphia’ chromosome, where
chromosomes 9 and 22 all appear to be normal, but
89
Chronic myelogenous leukaemia (CML)
where cryptic insertion of 3’ ABL
chromosome 22 can be demonstrated.
Huret JL
within
a
Results of the chromosomal
anomaly
Additional anomalies
1. May be present at diagnosis (in 10%, possibly with
unfavourable significance), or may appear during
course of the disease, they do not indicate the
imminence of a blast crisis, although these additional
anomalies also emerge frequently at the time of acute
transformation;
2. these are: +der(22), +8, i(17q), +19, most often, but
also: +21, -Y, -7, -17, +17; acute transformation can
also be accompanied with t(3;21)(q26;q22) (1% of
cases); near haploidy can occur; of note, although rare,
is the occurrence of chromosome anomalies which are
typical of a given BC phenotype (e.g. t(15;17) in a
promyelocytic transformation, dic(9;12) in a CD10+
lymphoblastic BC...); +8, +19, +21, and i(17q) occur
more often in myeloid -rather than lymphoid- blast
crises.
Hybrid gene
Description
1. The crucial event lies on der(22), id est 5’ BCR/3’
ABL hybrid gene is pathogenic, while ABL/BCR may
or may not be expressed;
2. Breakpoint in ABL is variable over a region of 200
kb, often between the two alternative exons 1b and 1a,
sometimes 5’ of 1b, or 3’ of 1a, but always 5’ of exon
2;
3. Breakpoint in BCR is in a narrow region, therefore
called M-bcr (for major breakpoint cluster region), a
cluster of 5.8 kb, between exons 12 and 16, also called
b1 to b5 of M-bcr; most breakpoints being either
between b2 and b3, or between b3 and b4.
Transcript
8.5 kb mRNA, resulting in a 210 kDa chimeric protein.
Detection protocol
RT-PCR for minimal residual disease detection.
Variants
t(9;22;V) and apparent t(V;22) or t(9;V), where V is a
variable chromosome, are found in 5-10% of cases;
however, 9q34-3’ABL always joins 22q11-5’BCR in
true CML; the third chromosome and breakpoint is, at
times, not random. In a way, masked Philadelphia
chromosomes (see above) are also variants.
Fusion protein
Description
P210 with the first 902 or 927 amino acids from BCR;
BCR/ABL has a cytoplasmic localization, in contrast
with ABL, mostly nuclear. It is now clearly established
that BCR-ABL is the oncogene responsible for the
occurrence of CML. The hybrid protein has an
increased protein kinase activity compared to ABL:
3BP1 (binding protein) binds normal ABL on SH3
domain, which prevents SH1 activation; with
BCR/ABL, the first (N-terminal) exon of BCR binds to
SH2, hidding SH3 which, as a consequence, cannot be
bound to 3BP1; thereof, SH1 is activated.
Oncogenesis
1. Proliferation is induced: there is activation by
BCR/ABL of Ras signal transduction pathway via it’s
linkage to son-of-sevenless (SOS), a Ras activator; PI3K (phosphatidyl inositol 3’ kinase) pathway is also
activated; MYC as well;
2. BCR/ABL inhibits apoptosis;
3. BCR/ABL provokes cell adhesive abnormalities:
impaired adherence to bone marrow stroma cells,
which allows unregulated proliferation of leukaemic
progenitors.
Genes involved and Proteins
ABL
Location: 9q34
DNA / RNA
Alternate splicing (1a and 1b) in 5’.
Protein
Giving rise to 2 proteins of 145 kDa; contains SH (SRC
homology) domains; N-term SH3 and SH2 - SH1
(tyrosine kinase) - DNA binding motif - actin binding
domain C-term; widely expressed; localisation is
mainly nuclear; inhibits cell growth.
BCR
Location: 22q11
DNA / RNA
Various splicings.
Protein
Main form: 160 kDa; N-term Serine-Threonine kinase
domain, SH2 binding, and C-term domain which
functions as a GTPase activating protein for p21rac;
widely expressed; cytoplasmic localisation; protein
kinase; probable role in signal transduction.
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
To be noted
1. Blast crisis is sometimes at the first onset of CML,
and those cases may be undistinguishable from true
ALL or ANLL with t(9;22) and P210 BCR/ABL
hybrid;
90
Chronic myelogenous leukaemia (CML)
Huret JL
2. JCML (juvenile chronic myelogenous leukaemia) is
not the juvenile form of chronic myelogenous
leukaemia: there is no t(9;22) nor BCR/ABL hybrid in
JCML, and clinical features (including a worse
prognosis) are not similar to those found in CML;
3. So called BCR/ABL negative CML should not be
called so!
4. P53 is altered in 1/3 of BC-CML cases.
Kurzrock R, Talpaz M. The molecular pathology of chronic
myelogenous leukemia. Br J Haematol 1991;79 Suppl 1:34-37.
(Review).
References
Enright H, McGlave PB. Chronic myelogenous leukemia. Curr
Opin Hematol 1995;2:293-299. (Review).
Sokal JE, Gomez GA, Baccarani M, Tura S, ClarksonBD,
Cervantes F, Rozman C, Carbonell F, Anger B, Heimpel H, et
al. Prognostic significance of additional cytogenetic
abnormalities at diagnosis of Philadelphia chromosomepositive chronic granulocytic leukemia. Blood 1988;72:294298.
Gotoh A, Broxmeyer HE. The function of BCR/ABL and related
proto-oncogenes. Curr Opin Hematol 1997;4:3-11. (Review).
Martiat P, Michaux JL, Rodhain J. Philadelphia-negative (Ph-)
chronic myeloid leukemia (CML): comparison with Ph+ CML
and chronic myelomonocytic leukemia. The Groupe Francais
de Cytogenetique Hematologique. Blood 1991;78:205-112.
Gale RP, Grosveld G, Canaani E, Goldman JM. Chronic
myelogenous leukemia: biology and therapy. Leukemia
1993;7:653-658.
Guilhot F, Chastang C, Michallet M, Guerci A, Harousseau JL,
Maloisel F, Bouabdallah R, Guyotat D, Cheron N, Nicolini F,
Abgrall JF, Tanzer J. Interferon alfa-2b combined with
cytarabine versus interferon alone in chronic myelogenous
leukemia. French Chronic Myeloid Leukemia Study Group. N
Engl J Med 1997;337:223-229.
Huret JL. Complex translocations, simple variant translocations
and Ph-negative cases in chronic myelogenous leukaemia.
Hum Genet 1990;85:565-568. (Review).
This article should be referenced as such:
Heisterkamp N, Groffen J. Molecular insights into the
Philadelphia translocation. Hematol Pathol 1991;5:1-10.
(Review).
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
Huret JL. Chronic myelogenous leukaemia (CML). Atlas Genet
Cytogenet Oncol Haematol.1997;1(2):89-91.
91
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Short Communication
t(2;5)(p23;q35)
Jean-Loup Huret
Genetics, Department of Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021
Poitiers, France
Published in Atlas Database: December 1997
Online version is available at: http://AtlasGeneticsOncology.org/Anomalies/t0205.html
DOI: 10.4267/2042/32068
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Clinics and pathology
Genes involved and Proteins
Disease
ALK
High grade NHL.
Phenotype / cell stem origin
T-cell in 80%, or null-cell type; B-cell rarely; CD30+
in most cases; present with some overlapping features
with Hodgkin’s disease: CD30 positivity and ReedSternberg like cells, but t(2;5) is not found in
Hodgkin’s disease (still debated).
Epidemiology
10% of NHL; found in children and young adults;
median around 16 yrs.
Clinics
Involve lymph nodes and extra nodal sites such as
lungs and gastro intestinal tract.
Cytology
t(2;5) is found in about 30-50% of anaplastic large cell
NHL (also called ALCL); may be found in diffuse
large cell NHL or immunoblastic NHL; cases may be
misdiagnosed, as the malignant cells display a
pleomorphic appearance.
Prognosis
Although t(2;5) is found in aggressive high grade
tumours, a 80% five yr survival seems to be associated
with this anomaly.
Location: 2p23
Protein
After glycosylation, produces a glycoprotein;
membrane associated tyrosine kinase receptor.
NPM1
Location: 5q35
Protein
Nuclear localisation; binds to single and double strand
nucleic acids: RNA binding phosphoprotein.
Results of the chromosomal
anomaly
Hybrid gene
Description
5’ NPM-3’ ALK on der(5).
Transcript
2.4 kb.
Fusion protein
Description
75-80 kDa; 680 amino acids; the 117 N-term amino
acids from NPM are fused to the 563 C-term amino
acids of ALK (i.e. the entire cytoplasmic portion of
ALK); no apparent expression of the ALK/NPM
counterpart.
Expression localisation
Both in the cytoplasm and in the nucleus (nucleoplasm
and nucleolus).
Oncogenesis
Via the kinase function activated by oligomerization of
NPM-ALK mediated by the NPM part.
Cytogenetics
Additional anomalies
Most often present.
Variants
Have been described: with 5q35 involvement and
another partner chromosome.
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
92
t(2;5)(p23;q35)
Huret JL
References
lymphomas of T-cell phenotype, and in Hodgkin’s disease.
Blood 1995 Sep 15;86(6):2321-8.
Mason DY, Bastard C, Rimokh R, Dastugue N, Huret JL,
Kristoffersson U, Magaud JP, Nezelof C, Tilly H, Vannier JP, et
al. CD30-positive large cell lymphomas (‘Ki-1 lymphoma’) are
associated with a chromosomal translocation involving 5q35.
Br J Haematol 1990 Feb;74(2):161-8.
Bischof D, Pulford K, Mason DY, Morris SW. Role of the
nucleophosmin (NPM) portion of the non-Hodgkin’s lymphomaassociated NPM-anaplastic lymphoma kinase fusion protein in
oncogenesis. Mol Cell Biol 1997 Apr;17(4):2312-25.
Donner LR. Cytogenetics of lymphomas: a brief review of its
theoretical and practical significance. Cancer Genet Cytogenet
1997 Mar;94(1):20-6.
Morris SW, Kirstein MN, Valentine MB, Dittmer KG, Shapiro
DN, Saltman DL, Look AT. Fusion of a kinase gene, ALK, to a
nucleolar protein gene, NPM, in non-Hodgkin’s lymphoma.
Science 1994 Mar 4;263(5151):1281-4.
This article should be referenced as such:
Huret JL. t(2;5)(p23;q35). Atlas Genet Cytogenet Oncol
Haematol.1997;1(2):92-93.
Wellmann A, Otsuki T, Vogelbruch M, Clark HM, Jaffe ES,
Raffeld M. Analysis of the t(2;5)(p23;q35) translocation by
reverse transcription-polymerase chain reaction in CD30+
anaplastic large-cell lymphomas, in other non-Hodgkin’s
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
93
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Mini Review
t(4;11)(q21;q23)
Jean-Loup Huret
Genetics, Department of Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021
Poitiers, France
Published in Atlas Database: December 1997
Online version is available at: http://AtlasGeneticsOncology.org/Anomalies/t0411.html
DOI: 10.4267/2042/32069
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
t(4;11)(q21;q23) ) G-banding (left) - Courtesy Diane H. Norback, Eric B. Johnson, and Sara Morrison-Delap, UW Cytogenetic Services;
R-banding (right) - Editor (above), and Courtesy Christiane Charrin (below).
secondary to epipodophyllotoxins (antitopoisomerase
drugs for various cancers treatment); high WBC
(median
around
200
X
109/l),
anaemia,
thrombocytopenia; 90% blasts in blood.
Cytology
Typically CD19+; may be accompanied with myeloid
markers.
Treatment
Bone marrow transplantation is highly indicated, as the
prognosis is very poor.
Prognosis
CR is obtained but is promptly followed by relape;
median survival: 7 mths in adult cases, 9 mths in
children.
Clinics and pathology
Disease
ALL mainly.
Phenotype / cell stem origin
B-ALL (L1 or L2), biphenotypic AL, at times ANLL
(M4/M5 types mainly); has been found in treatment
related leukaemia; T-ALL as an exception.
Epidemiology
Children (including infants: named a congenital
leukaemia when before 1 yr or 2 yrs of age) and adults;
half cases are under 4 yrs, 1/3 under 1 yr; unbalanced
sex ratio in cases < 4 yrs (1M/2F); 2 to 5% of ALL.
Clinics
Organomegaly, CNS involvement not rare; can be
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
94
t(4;11)(q21;q23)
Huret JL
Cytogenetics
Results of the chromosomal
anomaly
Additional anomalies
In ¼ of cases at diagnosis, clonal evolution to
hyperploidy: i(7q) in 10%, +X, +Mar, +6, +8, +19,
+21, +13, +10, +14; no difference in outcome.
Hybrid gene
Description
5’ MLL - 3’ AF4; variable breakpoints.
Transcript
12 kb
Variants
Three way complex t(4;11;Var) exist and showed that
the crucial event lies on der(11).
Fusion protein
Description
e.g. 2319 amino acids; 240 kDa; N-term AT hook and
DNA methyltransferase from MLL fused to AF4 Cterm; the reciprocal (AF4-MLL) may or may not be
expressed; quite similar to the MLL/ENL fusion
protein found with t(11;19).
Expression localisation
Nuclear localisation.
References
i(7q) R-banding - Editor.
Genes involved and Proteins
Lampert F, Harbott J, Ludwig WD, Bartram CR, Ritter J, Gerein
V, Neidhardt M, Mertens R, Graf N, Riehm H. Acute leukemia
with chromosome translocation (4;11): 7 new patients and
analysis of 71 cases. Blut 1987 Jun;54(6):325-35.
AF4
Location: 4q21
DNA / RNA
10.5-12 kb mRNA.
Protein
Contains a nuclear targeting sequence;
localisation; function: transcription activator.
Pui CH, Frankel LS, Carroll AJ, Raimondi SC, Shuster JJ,
Head DR, Crist WM, Land VJ, Pullen DJ, Steuber CP, et al.
Clinical characteristics and treatment outcome of childhood
acute lymphoblastic leukemia with the t(4;11)(q21;q23): a
collaborative study of 40 cases. Blood 1991 Feb 1;77(3):440-7.
Heerema NA, Arthur DC, Sather H, Albo V, Feusner J, Lange
BJ, Steinherz PG, Zeltzer P, Hammond D, Reaman GH.
Cytogenetic features of infants less than 12 months of age at
diagnosis of acute lymphoblastic leukemia: impact of the
11q23 breakpoint on outcome: a report of the Childrens
Cancer Group. Blood 1994 Apr 15;83(8):2274-84.
nuclear
MLL
Location: 11q23
DNA / RNA
21 exons, spanning over 100 kb; 13-15 kb mRNA.
Protein
431 kDa; contains two DNA binding motifs (a AT
hook, and Zinc fingers), a DNA methyl transferase
motif, a bromodomain; transcriptional regulatory
factor; nuclear localisation.
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
Schoch C, Rieder H, Freund M, Hoelzer D, Riehm H, Fonatsch
C. Twenty-three cases of acute lymphoblastic leukemia with
translocation t(4;11)(q21;q23): the implication of additional
chromosomal aberrations. Ann Hematol 1995 Apr;70(4):195201.
This article should be referenced as such:
Huret JL. t(4;11)(q21;q23). Atlas Genet Cytogenet Oncol
Haematol.1997;1(2):94-95.
95
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Mini Review
t(9;11)(p22;q23)
Jean-Loup Huret
Genetics, Department of Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021
Poitiers, France
Published in Atlas Database: December 1997
Online version is available at: http://AtlasGeneticsOncology.org/Anomalies/t0911.html
DOI: 10.4267/2042/32070
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
t(9;11)(p22;q23) G-banding (left) - Courtesy Jean-Luc Lai and Alain Vanderhaegen; R-banding: center below: t(9;11)+der(9)t(9;11) Courtesy Christiane Charrin; t(9;22)(center above) and FISH (right) - Courtesy Pascale Cornillet-Lefebvre and Stéphanie Struski. The
probe is MLL; one signal is on the normal 11, one signal on the der(11), and one signal (arrow) on the der(9).
Epidemiology
2 to 5 % of ANLL; up to 25% of de novo M5a in
children; all ages represented; sex ratio: 1M/1F.
Clinics
Organomegaly, frequent CNS involvement, especially
in de novo cases; no preceding myelodysplastic phase,
unlike classic therapy related ANLL with chromosome
5 and/or 7 involvement, short interval from initial drug
therapy (may even be of 1-2 yrs).
Clinics and pathology
Disease
ANLL
Phenotype / cell stem origin
M5 most often (especially M5a), M4; de novo and;
therapy related ANLL with antitopoisomerase II drugs
(epipodophyllotoxins; anthracyclins, actinomycin D).
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
96
t(9;11)(p22;q23)
Huret JL
bromodomain;
nuclear.
Cytology
Absence of trilineage dysplasia, unlike classic therapy
related ANLL.
Prognosis
CR in most de novo ANLL cases; the prognosis may
not be as poor as in other 11q23 leukaemias, with a
median survival around 4 yrs in de novo cases; very
poor prognosis in secondary ANLL cases.
regulatory
factor;
Results of the chromosomal
anomaly
Hybrid gene
Description
5’ MLL - 3’ AF9; variable breakpoints.
Cytogenetics
Fusion protein
Cytogenetics, morphological
Description
N-term -- AT hook and DNA methyltransferase from
MLL (1444 amino acids) fused to the 192 C-term
amino acids from AF9 (as breakpoints are variable, this
is only an exemple); 180 kDa.
Expression localisation
Nuclear localisation.
May easily be overlooked; better seen using R-banding.
Cytogenetics, molecular
FISH is indicated.
Additional anomalies
None in 70% of cases, +8 in 20%.
Variants
References
Complex 3 way translocations t(9;11;Var) involving a
(variable) third chromosome have been described, and
showed that der(11) is the crucial one.
Albain KS, Le Beau MM, Ullirsch R, Schumacher H. Implication
of prior treatment with drug combinations including inhibitors of
topoisomerase II in therapy-related monocytic leukemia with a
9;11 translocation. Genes Chromosomes Cancer 1990
May;2(1):53-8.
Genes involved and Proteins
Sandoval C, Head DR, Mirro J Jr, Behm FG, Ayers GD,
Raimondi SC. Translocation t(9;11)(p21;q23) in pediatric de
novo and secondary acute myeloblastic leukemia. Leukemia
1992 Jun;6(6):513-9.
AF9
Location: 9p22
Protein
Contains a nuclear targeting sequence; transcriptional
activator; nuclear localisation.
Joh T, Kagami Y, Yamamoto K, Segawa T, Takizawa J,
Takahashi T, Ueda R, Seto M. Identification of MLL and
chimeric MLL gene products involved in11q23 translocation
and possible mechanisms of leukemogenesis by MLL
truncation. Oncogene 1996 Nov 7;13(9):1945-53.
MLL
Location: 11q23
Protein
Contains two DNA binding motifs (a AT hook, and
Zinc fingers), a DNA methyl transferase motif, a
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
transcriptional
This article should be referenced as such:
Huret JL. t(9;11)(p22;q23). Atlas Genet Cytogenet Oncol
Haematol.1997;1(2):96-97.
97
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Mini Review
t(9;22)(q34;q11) in CML
Jean-Loup Huret
Genetics, Department of Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021
Poitiers, France
Published in Atlas Database: December 1997
Online version is available at: http://AtlasGeneticsOncology.org/Anomalies/t0922CML.html
DOI: 10.4267/2042/32071
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Note: Although the same hybrid genes issued from ABL and BCR are the hallmark of the t(9;22) translocation, this
translocation may be seen in the following diseases: CML, ANLL, and ALL, and will therefore be described in the 3
different situations: t(9;22)(q34;q11) in CML, t(9;22)(q34;q11) in ALL, t(9;22)(q34;q11) in ANLL.
t(9;22)(q34;q11) in CML is herein described.
q11
q12
q13
q34
9
22
accelerated phase(s)(blasts still < 15%), and blast crisis
(BC-CML) with blast cells > 30%; blood data: WBC:
100 X 109/l and more during chronic phase, with
basophilia; a few blasts; thrombocytosis may be
present; low leucocyte alkaline phosphatases; typical
acute leukaemia (AL) blood data at the time of myeloid
or lymphoid-type blast crisis.
Cytology
Hyperplastic bone marrow; granulocytes proliferation,
with maturation; followed by typical AL cytology (see
t(9;22)(q34;q11)/ANLL, and t(9;22)(q34;q11)/ALL).
Treatment
AlphaIFN therapy or bone marrow transplantation
(BMT), donor leukocytes infusions.
Prognosis
Median survival: 4 yrs with conventional therapy
(hydroxyurea, busulfan), 6 yrs with alphaIFN therapy;
bone marrow transplantation may cure the patient;
Clinics and pathology
Disease
CML: all CML have a t(9;22), at least at the molecular
level (see below); but not all t(9;22) are found in CML,
as already noted.
Phenotype / cell stem origin
Multipotent (and primitive: CD34+, DR-) progenitor:
t(9;22) is found in any myeloid progenitor and in Blymphocytes progenitors, but, most often, not in the Tcells.
Epidemiology
Annual incidence: 10/106 (from 1/106 in childhood to
30/106 after 60 yrs); median age: 30-60 yrs; sex ratio:
1.2M/1F.
Clinics
Splenomegaly; chronic phase (lasts about 3 yrs) with
maintained cell’s normal activities, followed by
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
98
t(9;22)(q34;q11) in CML
Huret JL
otherwise, the best treatment to date associates
interferon alpha, hydroxyurea and cytarabine.
DNA / RNA
Various splicings.
Protein
Main form: 160 kDa; N-term Serine-Threonine kinase
domain, SH2 binding, and C-term domain which
functions as a GTPase activating protein for p21rac;
widely expressed; cytoplasmic localisation; protein
kinase; probable role in signal transduction.
Cytogenetics
Cytogenetics, morphological
The chromosomal anomaly persists during remission,
in contrast with AL cases.
Cytogenetics, molecular
Results of the chromosomal
anomaly
Is a useful tool for diagnostic ascertainment in the case
of a ‘masked Philadelphia’ chromosome, where
chromosomes 9 and 22 all appear to be normal, but
where cryptic insertion of 3’ ABL within a
chromosome 22 can be demonstrated.
Hybrid gene
Description
1- The crucial event lies on der(22), id est 5’ BCR/3’
ABL hybrid gene is pathogenic, while ABL/BCR may
or may not be expressed;
2- Breakpoint in ABL is variable over a region of 200
kb, often between the two alternative exons 1b and 1a,
sometimes 5’ of 1b or 3’ of 1a, but always 5’ of exon 2;
3- Breakpoint in BCR is in a narrow region, therefore
called M-bcr (for major breakpoint cluster region), a
cluster of 5.8 kb, between exons 12 and 16, also called
b1 to b5 of M-bcr; most breakpoints being either
between b2 and b3, or between b3 and b4.
Transcript
8.5 kb mRNA, resulting in a 210 kDa chimeric protein.
Detection protocole
RT-PCR for minimal residual disease detection.
Additional anomalies
1- May be present at diagnosis (in 10%, possibly with
unfavourable significance), or may appear during
course of the disease, they do not indicate the
imminence of a blast crisis, although these additional
anomalies also emerge frequently at the time of acute
transformation;
2- These are: +der(22), +8, i(17q), +19, most often, but
also: +21, -Y, -7, -17, +17; acute transformation can
also be accompanied with t(3;21)(q26;q22) (1% of
cases); near haploidy can occur; of note, although rare,
is the occurrence of chromosome anomalies which are
typical of a given BC phenotype (e.g. t(15;17) in a
promyelocytic transformation, dic(9;12) in a CD10+
lymphoblastic BC...); +8, +19, +21, and i(17q) occur
more often in myeloid -rather than lymphoid- blast
crises.
Fusion protein
Variants
Description
P210 with the first 902 or 927 amino acids from BCR;
BCR/ABL has a cytoplasmic localization, in contrast
with ABL, mostly nuclear; this may have a
carcinogenetic role. The hybrid protein has an
increased protein kinase activity compared to ABL:
3BP1 (binding protein) binds normal ABL on SH3
domain, which prevents SH1 activation; with
BCR/ABL, the first (N-terminal) exon of BCR binds to
SH2, hidding SH3 which, as a consequence, cannot be
bound to 3BP1; thereof, SH1 is activated.
Oncogenesis
t(9;22;V) and apparent t(V;22) or t(9;V), where V is a
variable chromosome, are found in 5-10% of cases;
however, 9q34-3’ABL always joins 22q11-5’BCR in
true CML; the third chromosome and breakpoint is, at
times, not random. In a way, masked Philadelphia
chromosomes (see above) are also variants.
Genes involved and Proteins
ABL
Location: 9q34
DNA / RNA
Alternate splicing (1a and 1b) in 5’.
Protein
Giving rise to 2 proteins of 145 kDa; contains SH (SRC
homology) domains; N-term SH3 and SH2 - SH1
(tyrosine kinase) - DNA binding motif - actin binding
domain C-term; widely expressed; localisation is
mainly nuclear; inhibits cell growth.
1- Proliferation is induced: there is activation by
BCR/ABL of Ras signal transduction pathway via it’s
linkage to son-of-sevenless (SOS), a Ras activator; PI3K (phosphatidyl inositol 3’ kinase) pathway is also
activated; MYC as well;
2- BCR/ABL inhibits apoptosis;
3- BCR/ABL provokes cell adhesive abnormalities:
impaired adherence to bone marrow stroma cells,
which allows unregulated proliferation of leukaemic
progenitors.
BCR
Location: 22q11
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
99
t(9;22)(q34;q11) in CML
Huret JL
Heisterkamp N, Groffen J. Molecular insights into the
Philadelphia translocation. Hematol Pathol 1991;5:1-10.
(Review).
To be noted
Specific comments on this translocation:
1- Blast crisis is sometimes at the first onset of CML,
and those cases may be undistinguishable from true
ALL or ANLL with t(9;22) and P210 BCR/ABL
hybrid;
2- JCML (juvenile chronic myelogenous leukaemia) is
not the juvenile form of chronic myelogenous
leukaemia: there is no t(9;22) nor BCR/ABL hybrid in
JCML, and clinical features (including a worse
prognosis) are not similar to those found in CML;
3- So called BCR/ABL negative CML should not be
called so!
4- P53 is altered in 1/3 of BC-CML cases.
Kurzrock R, Talpaz M. The molecular pathology of chronic
myelogenous leukemia. Br J Haematol 1991;79 Suppl 1:34-37.
(Review).
Martiat P, Michaux JL, Rodhain J. Philadelphia-negative (Ph-)
chronic myeloid leukemia (CML): comparison with Ph+ CML
and chronic myelomonocytic leukemia. The Groupe Français
de Cytogénétique Hématologique. Blood 1991;78:205-112.
Gale RP, Grosveld G, Canaani E, Goldman JM. Chronic
myelogenous leukemia: biology and therapy. Leukemia
1993;7:653-658.
Enright H, McGlave PB. Chronic myelogenous leukemia. Curr
Opin Hematol 1995;2:293-299. (Review).
Gotoh A, Broxmeyer HE. The function of BCR/ABL and related
proto-oncogenes. Curr Opin Hematol 1997;4:3-11. (Review).
Guilhot F, Chastang C, Michallet M, Guerci A, Harousseau JL,
Maloisel F, Bouabdallah R, Guyotat D, Cheron N, Nicolini F,
Abgrall JF, Tanzer J. Interferon alfa-2b combined with
cytarabine versus interferon alone in chronic myelogenous
leukemia. French Chronic Myeloid Leukemia Study Group. N
Engl J Med 1997;337:223-229.
References
Sokal JE, Gomez GA, Baccarani M, Tura S, Clarkson BD,
Cervantes F, Rozman C, Carbonell F, Anger B, Heimpel H, et
al. Prognostic significance of additional cytogenetic
abnormalities at diagnosis of Philadelphia chromosomepositive chronic granulocytic leukemia. Blood 1988;72:294298.
This article should be referenced as such:
Huret JL. t(9;22)(q34;q11) in CML. Atlas Genet Cytogenet
Oncol Haematol.1997;1(2):98-100.
Huret JL. Complex translocations, simple variant translocations
and Ph-negative cases in chronic myelogenous leukemia. Hum
Genet 1990;85:565-568. (Review).
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
100
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Short Communication
t(10;11)(p12;q23)
Jean-Loup Huret
Genetics, Department of Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021
Poitiers, France
Published in Atlas Database: December 1997
Online version is available at: http://AtlasGeneticsOncology.org/Anomalies/t1011.html
DOI: 10.4267/2042/32072
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology
MLL
Identity
Note: Not to be
t(10;11)(p14;q21).
confused
with
cases
Location: 11q23
DNA / RNA
21 exons, spanning over 100 kb; 13-15 kb mRNA.
Protein
431 kDa; contains two DNA binding motifs (a AT
hook, and Zinc fingers), a DNA methyl transferase
motif, a bromodomain; transcriptional regulatory
factor; nuclear localisation.
of
Clinics and pathology
Disease
ANLL.
Phenotype / cell stem origin
M5/M4; ALL at times, therapy related cases.
Epidemiology
From infants to adults.
Prognosis
Poor.
Results of the chromosomal
anomaly
Hybrid gene
Description
5’ MLL - 3’ AF10; variable breakpoints on both
chromosomes; the fusion transcript on chromosome 11
is the crucial one; MLL and AF10 are in opposite
transcriptional directions, which may be cause of the
complexity of the translocation.
Cytogenetics
Cytogenetics, morphological
A high diversity of reported breakpoints on
chromosome 10, from 10p11 to 10p15: remains to be
fully studied.
Fusion protein
inv(11)(q13q23) is frequently accompanying the
t(10;11); this is likely to be related to the transcription
directions of the two genes.
Description
N-term AT hook and DNA methyltransferase from
MLL fused to the leucine zipper C-term of AF10.
Expression localisation
Nuclear localisation.
Genes involved and Proteins
References
AF10
Chaplin T, Bernard O, Beverloo HB, Saha V, Hagemeijer A,
Berger R, Young BD. The t(10;11) translocation in acute
myeloid leukemia (M5) consistently fuses the leucine zipper
motif of AF10 onto the HRX gene. Blood 1995 Sep
15;86(6):2073-6.
Additional anomalies
Location: 10p12
DNA / RNA
5’ telomeric → 3’ centromeric orientation.
Protein
Contains 3 Zn fingers and a leucine zipper; nuclear
localisation; transcription factor.
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
This article should be referenced as such:
Huret JL. t(10;11)(p12;q23). Atlas Genet Cytogenet Oncol
Haematol.1997;1(2):101.
101
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Mini Review
t(11;19)(q23;p13.1)
Jean-Loup Huret
Genetics, Department of Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021
Poitiers, France
Published in Atlas Database: December 1997
Online version is available at: http://AtlasGeneticsOncology.org/Anomalies/t1119ELL.html
DOI: 10.4267/2042/32073
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Note: Two different translocations (and two clinical entities), both involving 11q23 with a common breakpoint in MLL,
and 19p13 with different breakpoints are now identified: the above mentioned, and the t(11;19)(q23;p13.3).
t(11;19)(q23;p13.1); G-banding (left) and R banding (right)(top: - Editor; below: - Courtesy Christiane Charrin).
Clinics and pathology
Cytogenetics
Disease
Cytogenetics, morphological
ANLL.
Phenotype / cell stem origin
M4/M5 most often; M1/M2 at times; therapy related
AL; however, clonal rearrangements of IgH gene have
been found, demonstrating a biphenotypic nature.
Epidemiology
Children and, most often, adults (7 days to 83 yrs);
congenital cases are rare, in contrast with the
t(11;19)(q23;p13.3) leukaemia; balanced sex ratio.
Clinics
Organomegaly in half cases; CNS involvement in some
cases.
Treatment
BMT is indicated.
Prognosis
Very poor (median: 6 mths!).
Can be seen with R-banding: chromosome 11 appears
enlarged, chromosome 19 shortened (11q+ and 19p-);
will be missed with G-banding.
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
Cytogenetics, molecular
Therefore, FISH may be needed.
Additional anomalies
None at diagnosis in 2/3 cases; +8.
Genes involved and Proteins
MLL
Location: 11q23
DNA / RNA
21 exons, spanning over 100 kb; 13-15 kb mRNA.
Protein
431 kDa; contains two DNA binding motifs (a AT
hook, and Zinc fingers), a DNA methyl transferase
motif, a bromodomain; transcriptional regulatory
factor; nuclear localisation.
102
t(11;19)(q23;p13.1)
Huret JL
LAM5B ; Karyotype : 46,XX,t(11;19)(q23;p13.1); in situ hybridization with a 19 whole chromosome paint probe (spectrum green) and a
MLL dual color break apart rearrangement probe; the der(19) is WCP19-spectrum green+ and 3’-MLL spectrum orange+ - Courtesy
Pascaline Talmant.
ELL
To be noted
Location: 19p13.1
Protein
Contains a Lysin rich domain (basic motif); nuclear
localisation; transcription factor (RNA polymerase
elongation factor).
Shortly, both t(11;19): have a breakpoint in MLL in
11q23, a very poor prognosis, and may, in some cases
be treatment related leukaemias; but, while the above
described has a breakpoint in 19p13.1, is found only in
ANLL, involves ELL, is diagnosed with R-banding
(11q+ and 19p-) and missed with G-banding, the
translocation with a breakpoint in 19p13.3 can be seen
with G-banding (11q- and 19p+) and missed with Rbanding, involves ENL, and can be found in ALL,
biphenotypic leukaemias, and ANLL.
Results of the chromosomal
anomaly
Hybrid gene
Description
5’ MLL - 3’ ELL.
References
Huret JL, Brizard A, Slater R, Charrin C, Bertheas MF, Guilhot
F, Hählen K, Kroes W, van Leeuwen E, Schoot EV, et al.
Cytogenetic heterogeneity in t(11;19) acute leukemia: clinical,
hematological and cytogenetic analyses of 48 patients —
updated published cases and 16 new observations. Leukemia
1993 Feb;7(2):152-60. (Review).
Fusion protein
Description
AT hook and DNA methyltransferase from MLL fused
to most of ELL.
Expression localisation
Nuclear localisation.
Oncogenesis
Potential transcription factor.
Mitani K, Kanda Y, Ogawa S, Tanaka T, Inazawa J, Yazaki Y,
Hirai H. Cloning of several species of MLL/MEN chimeric
cDNAs in myeloid leukemia with t(11;19)(q23;p13.1)
translocation. Blood 1995 Apr 15;85(8):2017-24.
This article should be referenced as such:
Huret JL. t(11;19)(q23;p13.1). Atlas Genet Cytogenet Oncol
Haematol.1997;1(2):102-103.
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
103
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Mini Review
t(11;19)(q23;p13.3)
Jean-Loup Huret
Genetics, Department of Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021
Poitiers, France
Published in Atlas Database: December 1997
Online version is available at: http://AtlasGeneticsOncology.org/Anomalies/t1119ENL.html
DOI: 10.4267/2042/32074
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Note: two different translocations (and two clinical entities), both involving 11q23 with a common breakpoint in MLL,
and 19p13 with different breakpoints are now identified: the above mentioned, and the t(11;19)(q23;p13.1).
t(11;19)(q23;p13.3) G-banding left: Courtesy Jean-Luc Lai; middle and right: Courtesy Diane H. Norback, Eric B. Johnson, and Sara
Morrison-Delap, UW Cytogenetic Services.
Clinics and pathology
Disease
ALL, ANLL.
Phenotype / cell stem origin
B-cell ALL: L1/L2 CD19+, CD10- most often;
biphenotypic: CD19+ (B-cell) as well, but also with
myeloid markers; ANLL: M4/M5 mainly; therapy
related AL; T-cell ALL at times.
Epidemiology
Most cases are found in infants < 1 yr (congenital
leukaemia), whatever the phenotype except in T-cell
cases (children cases); such a feature is particularly
stricking; most female cases exhibit a B-lineage or
biphenotypic phenotype, most male cases are M4/M5
cases.
Clinics
Organomegaly, frequent CNS involvement (in Bcell/biphenotypic cases); blood data: high WBC.
Treatment
BMT is indicated.
Prognosis
Very poor (median < 1 yr), except in the rare T-cell
cases, who are, so far, long survivors.
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
Cytogenetics
Cytogenetics, morphological
Can be seen with G-banding: chromosome 11 appears
shortened, chromosome 19 enlarged (11q- and 19p+);
will be missed with R-banding.
104
t(11;19)(q23;p13.3)
Huret JL
Cytogenetics, molecular
Fusion protein
Therefore, FISH may be needed.
Expression localisation
AT hook and DNA methyltransferase from MLL fused
to, most often, the nearly entire ENL.
Additional anomalies
None in most cases; +X may be found in male and
female patients; +6, +8, +19.
To be noted
Variants
Shortly, both t(11;19): have a breakpoint in MLL in
11q23, a very poor prognosis, and may, in some cases
be treatment related leukaemias; but, while the above
described has a breakpoint in 19p13.3, can be seen with
G-banding (11q- and 19p+) and missed with Rbanding, involves ENL, and can be found in ALL,
biphenotypic leukaemias, and ANLL, the translocation
with a breakpoint in 19p13.1 involves ELL, is found
with R-banding (11q+ and 19p-) and missed with Gbanding, and only in ANLL.
Three way complex t(11;19;Var) exist, as well as
complex rearrangements and inversions, and are
frequent; they demonstrated that the crucial event lies
on der(11).
Genes involved and Proteins
MLL
Location: 11q23
DNA / RNA
21 exons, spanning over 100 kb; 13-15 kb mRNA.
Protein
431 kDa; contains two DNA binding motifs (a AT
hook, and Zinc fingers), a DNA methyl transferase
motif, a bromodomain; transcriptional regulatory
factor; nuclear localisation.
References
Tkachuk DC, Kohler S, Cleary ML. Involvement of a homolog
of Drosophila trithorax by 11q23 chromosomal translocations in
acute leukemias. Cell 1992 Nov 13;71(4):691-700.
Huret JL, Brizard A, Slater R, Charrin C, Bertheas MF, Guilhot
F, Hahlen K, Kroes W, van Leeuwen E, Schoot EV, et al.
Cytogenetic heterogeneity in t(11;19) acute leukemia: clinical,
hematological and cytogenetic analyses of 48 patients updated published cases and 16 new observations. Leukemia
1993 Feb;7(2):152-60. (Review).
ENL
Location: 19p13.3
Protein
Serine/proline; contains a nuclear targeting sequence;
wide expression; nuclear localisation; transcription
activator.
This article should be referenced as such:
Huret JL. t(11;19)(q23;p13.3). Atlas Genet Cytogenet Oncol
Haematol.1997;1(2):104-105.
Results of the chromosomal
anomaly
Hybrid gene
Description
5’ MLL - 3’ ENL.
Atlas Genet Cytogenet Oncol Haematol. 1997;1(2)
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