Download Leukaemia Section t(1;19)(q23;p13) TCF3/PBX1 Atlas of Genetics and Cytogenetics

Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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Short Communication
t(1;19)(q23;p13) TCF3/PBX1
Cristina N Alonso
Hematology-Oncology Department, Hospital Nacional de Pediatria Garrahan, Combate de los Pozos 1881Zip Code : 1245. Buenos Aires, Republica Argentina (CNA)
Published in Atlas Database: July 2012
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0119.html
DOI: 10.4267/2042/48472
This article is an update of :
Huret JL. t(1;19)(q23;p13). Atlas Genet Cytogenet Oncol Haematol 1997;1(2):74-75.
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2013 Atlas of Genetics and Cytogenetics in Oncology and Haematology
CD45dim, CD19pos, CD34neg, CD22pos/dim,
CD20dim/pos, CD24pos, TdTpos, CD10neg/dim,
cIgMpos, CD9pos, CD15neg, CD65neg, CD66cneg,
CD13neg, CD33neg.
Identity
Note
Balanced form: -1, -19, +der(1), +der(19); unbalanced
form: -19, +der(19).
Epidemiology
Disease
5% of ALL, or 20% of pre B ALL; found in children
and young adults (1-60 yrs, median: 10 yrs --> one of
the most frequent ALL in childhood (4-6%)); 3 male/4
female patients.
B
Lymphoblastic
leukemia/lymphoma
with
t(1;19)(q23;p13.3); E2A-PBX1 (TCF3-PBX1); mostly
found in ALL, L1/L2 type; exceptionally found in L3like ALL, T-ALL, NHL, or AML.
Clinics
Phenotype/cell stem origin
Moderate organomegaly; frequent CNS involvement;
blood data: high WBC (median 20 x 109/L); high LDH.
Most cases: 'pre B' (cIg+) ALL; may be cIg- or sIg+.
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.Clinics and pathology
Atlas Genet Cytogenet Oncol Haematol. 2013; 17(1)
45
t(1;19)(q23;p13) TCF3/PBX1
Alonso CN
c-PBX1 at 1q23 in normal cells: PAC 1146N1 - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics. Laboratories willing to
validate the probes are wellcome: contact M Rocchi.
Treatment
Genes involved and proteins
Treatment should be adapted to biological features at
the moment of diagnosis and also to early
chemotherapy response and risk group stratification
should not be based on TCF3-PBX1 detection.
Note
The following are (most often) involved, except in
some cases lacking the cIg expression:
PBX1 (pre-B-cell leukemia homeobox 1)
Prognosis
Location
1q23.3
Note
Previously known as "pre-B-cell leukemia transcription
factor 1".
DNA/RNA
Alternate splicing (variants 1, 2 and 3) (Acc Numbers:
NM_001204963.1,
NM_001204961.1
and
NM_002585.3).
Protein
Nuclear protein that belongs to the PBX homeobox
family of transcriptional factors. Contains a
homeodomain to bind to DNA.
Although this chromosomal abnormality usually
discloses adverse prognostic features (WBC, SNC), it
is associated with good prognosis with modern
intensive protocols.
Median 5 yr-event free survival probability in
childhood ALL: 85(6)%; no age or blood data
prognostic significance; there are no differences
between the prognosis of balanced or unbalanced
forms.
Prognosis in adults is not different between TCF3PBX1 positive and negative cases (pEFS: 40 vs. 44%).
Cytogenetics
Cytogenetics morphological
TCF3 (transcription factor 3)
Breakpoint is in 19p13.3; two different forms (see
diagrams above): - the balanced t(1;19), one fourth of
cases, with a der(1) and a der(19); - the unbalanced
form, found in 3/4 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). A
subset of ALL usually hyperdyploid B-ALL has an
identical t(1;19) that lack the expected phenotype
probably do not represent TCF3-PBX1 B-ALL.
Location
19p13.3
Note
Other names: bHLHb21, E2A, "E2A immunoglobulin
enhancer-binding
factor
E12/E47",
E47,
"immunoglobulin transcription factor 1", ITF1, "kappaE2-binding factor", MGC129647, MGC129648,
"transcription factor E2-alpha", VDIR, "VDR
interacting repressor".
DNA/RNA
Alternate splicing 2 isoforms --> E12 and E47.
Alternatively spliced transcript variants encoding
multiple isoforms have been observed for this gene,
and a pseudogene of this gene is located on the short
arm of chromosome 9.
Additional anomalies
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. Additional
anomalies are found in half of the cases, mostly partial
dup (1q), +6, del(6q), +8, i(9q), +17, i(17q), +21.
Atlas Genet Cytogenet Oncol Haematol. 2013; 17(1)
46
t(1;19)(q23;p13) TCF3/PBX1
Alonso CN
Different molecular consequences of the 1;19 chromosomal
translocation in childhood B-cell precursor acute lymphoblastic
leukemia. Blood. 1992 Apr 1;79(7):1781-8
Protein
Contains transcriptional activation domains and a basic
helix-loop-helix DNA binding site; binds specifically to
an immunoglobulin enhancer; nuclear localization;
transcription factor.
Secker-Walker LM, Berger R, Fenaux P, Lai JL, Nelken B,
Garson M, Michael PM, Hagemeijer A, Harrison CJ, Kaneko Y.
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
Result of the chromosomal
anomaly
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
Hybrid gene
Description
5' TCF3 exons fused to 3' PBX1; breakpoints are
clustered on both genes; the reciprocal 5' PBX1 - 3'
E2A is not transcribed.
Transcript
Most cases present fusion of exons 1-16 in TCF3 to
exons 4-9 in PBX1.
Alternative breakpoint in intron 4 of PBX1, not
detectable by standardized RT-PCR primers, has been
reported.
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
Troussard X, Rimokh R, Valensi F, Leboeuf D, Fenneteau O,
Guitard AM, Manel AM, Schillinger F, Leglise C, Brizard A.
Heterogeneity of t(1;19)(q23;p13) acute leukaemias. French
Haematological Cytology Group. Br J Haematol. 1995
Mar;89(3):516-26
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
Fusion protein
Description
550 amino acids; 85 kDa; N-term transcriptional
activation domains from TCF3 fused to the Hox
cooperative motif and homeodomain of C-term PBX1;
potent transcriptional activator.
Expression / Localisation
Nuclear localisation.
Oncogenesis
Pleiotropic transforming activity.
The resulting fusion protein (TCF3-PBX1), in which
the DNA binding domain of E2A is replaced by the
DNA binding domain of TCF3, transforms cells by
constitutively activating transcription of genes
regulated by PBX1 or by other members the PBX
protein family.
Pui CH, Evans WE. Acute lymphoblastic leukemia. N Engl J
Med. 1998 Aug 27;339(9):605-15
Uckun FM, Sensel MG, Sather HN, Gaynon PS, Arthur DC,
Lange BJ, Steinherz PG, Kraft P, Hutchinson R, Nachman JB,
Reaman GH, Heerema NA. Clinical significance of
translocation t(1;19) in childhood acute lymphoblastic leukemia
in the context of contemporary therapies: a report from the
Children's Cancer Group. J Clin Oncol. 1998 Feb;16(2):527-35
Hrusák O, Porwit-MacDonald A. Antigen expression patterns
reflecting genotype of acute leukemias. Leukemia. 2002
Jul;16(7):1233-58
Faderl S, Jeha S, Kantarjian HM. The biology and therapy of
adult acute lymphoblastic leukemia. Cancer. 2003 Oct
1;98(7):1337-54
Prima V, Gore L, Caires A, Boomer T, Yoshinari M, Imaizumi
M, Varella-Garcia M, Hunger SP. Cloning and functional
characterization of MEF2D/DAZAP1 and DAZAP1/MEF2D
fusion proteins created by a variant t(1;19)(q23;p13.3) in acute
lymphoblastic leukemia. Leukemia. 2005 May;19(5):806-13
References
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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):547-55
Burmeister T, Gokbuget N, Schwartz S, Fischer L, Hubert D,
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Mellentin JD, Nourse J, Hunger SP, Smith SD, Cleary ML.
Molecular analysis of the t(1;19) breakpoint cluster region in
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lymphoblastic
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Genes
Chromosomes Cancer. 1990 Sep;2(3):239-47
Nourse J, Mellentin JD, Galili N, Wilkinson J, Stanbridge E,
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a potential chimeric transcription factor. Cell. 1990 Feb
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Felice MS, Gallego MS, Alonso CN, Alfaro EM, Guitter MR,
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This article should be referenced as such:
Alonso CN. t(1;19)(q23;p13) TCF3/PBX1.
Cytogenet Oncol Haematol. 2013; 17(1):45-47.
Privitera E, Kamps MP, Hayashi Y, Inaba T, Shapiro LH,
Raimondi SC, Behm F, Hendershot L, Carroll AJ, Baltimore D.
Atlas Genet Cytogenet Oncol Haematol. 2013; 17(1)
47
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