Download Gene Section MLL (myeloid/lymphoid or mixed lineage leukemia) Atlas of Genetics and Cytogenetics

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Gene Section
Mini Review
MLL (myeloid/lymphoid or mixed lineage
leukemia)
Rolf Marschalek
Institute of Pharmaceutical Biology, Biocenter N230, University of Frankfurt/Main, Marie-Curie-Str. 9, D60439 Frankfurt/Main, Germany (RM)
Published in Atlas Database: November 2002
Online updated version : http://AtlasGeneticsOncology.org/Genes/MLL.html
DOI: 10.4267/2042/37925
This article is an update of :
Hess JL, Huret JL. MLL (myeloid/lymphoid or mixed lineage leukemia). Atlas Genet Cytogenet Oncol Haematol.2001;5(1):11-13.
Huret JL. MLL (myeloid/lymphoid or mixed lineage leukemia). Atlas Genet Cytogenet Oncol Haematol.1997;1(2):68-69.
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2003 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Protein
Other names: ALL1; HRX; Htrx (human trithorax);
TRX1
HGNC (Hugo): MLL
Location: 11q23
Local order: Telomeric to PLZF, centromeric from
RCK.
Description
3969 amino acids; 431 KDa; contains two DNA
binding motifs: a AT hook homologous to high
mobility group proteins HMGI-(Y) and HMGI(C) that
binds to the minor groove of DNA, and zinc fingers, a
DNA methyl transferase motif, a bromodomain, and
segments of homology with trithorax, in particular in
the C-terminal SET domain.
Expression
Wide; especially in: brain, kidney, thyroid; expressed
in Taned B lymphocytes and myeloid cells.
Localisation
Nuclear, in punctate spots.
Function
MLL (11q23) - Courtesy Mariano Rocchi, Resources for
Molecular Cytogenetics.
Transcriptional regulatory factor,
maintenance of Hox gene expression.
DNA/RNA
in
Homology
Description
Trithorax (Drosophila), ALR (human), MLL2 (human).
37 exons, spanning over 100 kb.
Transcription
In a centromeric to telomeric direction; 13 and 15 kb;
coding sequence: 11.9 kb.
Atlas Genet Cytogenet Oncol Haematol. 2003; 7(1)
involved
16
MLL (myeloid/lymphoid or mixed lineage leukemia)
Marschalek R
MLL partner genes - Rolf Marschalek Nov 2002.
Mutations
Abnormal protein
240 kDa protein with about 1400 aminoacids from
NH2 MLL and 850 from COOH AF4 (variable
breakpoints); the reciprocal may or may not be
expressed.
Note
MLL is implicated in at least 10% of acute leukaemias
(AL) of various types: acute lymphoblastic leukemias
(ALL), acute non lymphocytic leukemias (ANLL),
biphenotypic ALs, treatment related leukemias, infant
leukemias; the prognosis is poor.
t(6;11)(q27;q23)/ANLL --> MLL/AF6
Disease
M5/M4 de novo and therapy related ANLL, T-cell
ALL.
Implicated in
t(9;11)(p22;q23)/ANLL -->MLL/AF9
t(4;11)(q21;q23)/acute leukaemias -->
MLL/AF4
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
Disease
Typically
CD19+
CD10-precursor
B-ALL,
biphenotypic AL, at times ANLL (M4/M5); common in
infants may be congenital; treatment related leukaemia
(secondary to epipodophyllotoxins).
Prognosis
Median survival <1yr.
Cytogenetics
Additional chromosome anomalies are found in 1/4 of
cases, one of which is the i(7q).
Hybrid/Mutated gene
5' MLL - 3' AF4; 12 kb.
Atlas Genet Cytogenet Oncol Haematol. 2003; 7(1)
17
MLL (myeloid/lymphoid or mixed lineage leukemia)
Marschalek R
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 example).
t(X;11)(q13;q23)/ANLL, T-ALL -->
MLL/AFX1
t(X;11)(q22;q23)/ANLL --> MLL/Septin2
t(1;11)(p32;q23)/ALL --> MLL/AF1p
t(1;11)(q21;q23)/ANLL --> MLL/AF1q
t(2;11)(q11;q23)/MDS --> MLL/LAF4
t(3;11)(p21;q23)/t-ANLL --> MLL/AF3p21
t(3;11)(q25;q23)/t-ANLL --> MLL/GMPS
ins(5;11)(q31;q13q23)/ALL -->
MLL/AF5q31
t(5;11)(q31;q23)/ANLL --> MLL/GRAF
t(6;11)(q21;q23)/ANLL --> MLL/AF6q21
t(9;11)(q34;q23)/ALL --> MLL/AF9q34
t(11;14)(q23;q24)/ANLL --> MLL/hgephyrin
t(11;15)(q23;q14)/ANLL -->
MLL/AF15q14
t(11;16)(q23;p13)/t-ANLL --> MLL/CBP
t(11;17)(q23;p13)/t-ANLL --> MLL/GAS7
t(11;17)(q23;q12)/ANLL --> MLL/RARa
t(11;17)(q23;q21)/ANLL --> MLL/AF17
t(11;17)(q23;q25)/ ANLL -->
MLL/MSF/AF17q25
t(11;19)(q23;p13)/ANLL --> MLL/EEN
t(11;22)(q23;q11.2)/ANLL -->
MLL/hCDCRel
t(11;22)(q23;q13)/ANLL --> MLL/P300
t(10;11)(p12;q23)/ANLL --> MLL/AF10
Disease
M4 or M5 ANLL; ALL at times; therapy related
ANLL.
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.
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.
To be noted
Note
The card on 11q23 rearrangements, gives an overview
on diseases implicating MLL.
Trisomy 11/ANLL --> MLL tandem
duplication
Atlas Genet Cytogenet Oncol Haematol. 2003; 7(1)
18
MLL (myeloid/lymphoid or mixed lineage leukemia)
Marschalek R
Breakpoints
Xq13 (AFX1)
Xq22 (Septin2)
22q13 (P300)
Xq24
1p32 (AF1P)
22q11 (hCD Crel)
21q11
1q21(AF1q)
20q13
1q32
19p13.3 (ENL)
2p21
19p13 (EEN)
2q11 (LAF4)
19p13.1(ELL)
2q37
18q23
3p21 (AF3p21)
18q12
3q25 (GMPS)
17q25 (MSF)
3q28 (LPP)
17q21 (RARA)
4q21 (AF4)
17q21 (LASP1)
5q31 (GRAF)
17q21 (AF17)
11q23(MLL)
17q11
5q31 (AF5q31)
17p13 (GAS7)
6q21 (AF6q21)
16p13 (CBP)
6q27 (AF6)
7q22
15q15 (not AF15)
7q32
15q15 (AF15)
8q11
8q24
15q14 (AF15q14)
9p23 (AF9)
15q14 (MPFY VE)
9p11
14q32
14q24 (gephy rin)
9q33
9q34 (AF9q34)
14q11
9q34 (FBP17)
12q24
12q13
12p13
10p12 (AF10)
10p11 (ABI1)
11q23 (LARG)
10q22 (TET1/LCX)
11q23 (CBL)
11q13
11q23 (MLL duplication)
11p15
Note
Spanning an 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.
References
Young BD, Saha V.. Chromosome abnormalities in leukaemia:
the 11q23 paradigm. Cancer Surv. 1996;28:225-45. (REVIEW)
Bernard OA, Berger R. Molecular basis of 11q23
rearrangements in hematopoietic malignant proliferations.
Genes Chromosomes Cancer. 1995 Jun;13(2):75-85
Waring PM, Cleary ML. Disruption of a homolog of trithorax by
11q23 translocations: leukemogenic and transcriptional
implications. Curr Top Microbiol Immunol. 1997;220:1-23
Schichman SA, Canaani E, Croce CM. Self-fusion of the ALL1
gene. A new genetic mechanism for acute leukemia. JAMA.
1995 Feb 15;273(7):571-6
Dimartino JF, Cleary ML. Mll rearrangements in
haematological malignancies: lessons from clinical and
biological studies. Br J Haematol. 1999 Sep;106(3):614-26
Nilson I, Löchner K, Siegler G, Greil J, Beck JD, Fey GH,
Marschalek R. Exon/intron structure of the human ALL-1 (MLL)
gene involved in translocations to chromosomal region 11q23
and acute leukaemias. Br J Haematol. 1996 Jun;93(4):966-72
Huntsman DG, Chin SF, Muleris M, Batley SJ, Collins VP,
Wiedemann LM, Aparicio S, Caldas C. MLL2, the second
human homolog of the Drosophila trithorax gene, maps to
19q13.1 and is amplified in solid tumor cell lines. Oncogene.
1999 Dec 23;18(56):7975-84
Rasio D, Schichman SA, Negrini M, Canaani E, Croce CM.
Complete exon structure of the ALL1 gene. Cancer Res. 1996
Apr 15;56(8):1766-9
This article should be referenced as such:
Marschalek R. MLL (myeloid/lymphoid or mixed lineage
leukemia). Atlas Genet Cytogenet Oncol Haematol. 2003;
7(1):16-19.
Rubnitz JE, Behm FG, Downing JR. 11q23 rearrangements in
acute leukemia. Leukemia. 1996 Jan;10(1):74-82
Atlas Genet Cytogenet Oncol Haematol. 2003; 7(1)
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