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

Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Review
MLL (myeloid/lymphoid or mixed lineage
leukemia)
Jean-Loup Huret
Genetics, Dept Medical Information, UMR 8125 CNRS, University of Poitiers, CHU Poitiers Hospital, F86021 Poitiers, France
Published in Atlas Database: October 2005
Online updated version: http://AtlasGeneticsOncology.org/Genes/MLL.html
DOI: 10.4267/2042/38290
This article is an update of:
Marschalek R. MLL (myeloid/lymphoid or mixed lineage leukemia). Atlas Genet Cytogenet Oncol Haematol.2003;7(1):16-18.
Hess JL, Huret JL. MLL (myeloid/lymphoid or mixed lineage leukemia). Atlas Genet Cytogenet Oncol Haematol.2001;5(1):12-14.
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-Non-commercial-No Derivative Works 2.0 France Licence.
© 2006 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Protein
Hugo: MLL
Other names: ALL1, HRX, Htrx (human trithorax),
TRX1
Location: 11q23
Local order: telomeric to PLZF, centromeric from
RCK.
Description
3969 amino acids; 431 KDa; contains from N-term to
C-term 3 AT hooks homologous to high mobility group
proteins HMGA1 and HMGA2, binding to the minor
grove of DNA; 2 speckled nuclear localisation signals;
2 repression domains RD1 and RD2: RD1 or CXXC:
cystein methyl transferase, binds CpG rich DNA, has a
transcriptional repression activity; RD2 recruits histone
desacetylases HDAC1 and 2; 3 plant homeodomains
(cystein
rich
zinc
finger
domains,
with
homodimerization properties), 1 bromodomain (may
bind acetylated histones), and 1 plant homeodomain;
these domains may be involved in protein-protein
interaction; a FYRN and a FRYC domain; a
transactivation domain which binds CBP; may
acetylates H3 and H4 in the HOX area; a SET domain:
methyltransferase; methyltates H3, including histones
in the HOX area for allowing chromatin to be open to
transcription. MLL is cleaved by taspase 1 into 2
proteins before entering the nucleus: a p300/320 Nterm protein called MLL-N, and a p180 C-term protein,
called MLL-C. The FYRN and a FRYC domains of
native MLL associate MLL-N and MLL-C in a stable
complex; they form a multiprotein complex with
transcription factor TFIID.
DNA/RNA
MLL (11q23) - Courtesy Mariano Rocchi, Resources for
Molecular Cytogenetics.
Description
37 exons, spanning over 100 kb
Transcription
In a centromeric to telomeric direction; 13 and 15 kb;
coding sequence: 11.9 kb
Expression
Wide; especially in: brain, kidney, thyroid; expressed
in Taned B lymphocytes and myeloid cells.
Atlas Genet Cytogenet Oncol Haematol. 2006;10(2)
83
MLL (myeloid/lymphoid or mixed lineage leukemia)
Huret JL
MLL partner genes - Rolf Marschalek Nov 2002.
Implicated in
Localisation
Nuclear, in punctate spots.
t(4;11)(q21;q23)/acute leukaemias →
MLL-AFF1 (AF4)
Function
Transcriptional regulatory factor; MLL may have yinyang functions though actions of MLL-N and MLL-C
(e.g. desacetylation/acetylation); MLL-N acts as a
transcriptional repressor; MLL can be associated with
more than 30 proteins, including the core components
of the SWI/SNF chromatin remodeling complex and
the transcription complex TFIID. MLL binds
promotors of HOX genes through acetylation and
methylation of histones. MLL is a major regulator of
hematopoesis and embryonic development, through
regulation of HOX genes expression regulation
(HOXA9 in particular).
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 < 1 year
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; 12kb.
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.
Homology
Trithorax (Drosophila), ALR (human), MLL2 (human).
Mutations
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.
Atlas Genet Cytogenet Oncol Haematol. 2006;10(2)
84
MLL (myeloid/lymphoid or mixed lineage leukemia)
Huret JL
t(6;11)(q27;q23)/ANLL → MLL-MLLT4
(AF6)
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 example).
Disease
M5/M4 de novo and therapy related ANLL, T-cell
ALL.
Prognosis
Poor.
t(9;11)(p22;q23) /ANLL → MLL-MLLT3
(AF9)
t(10;11)(p12;q23)/ANLL → MLL-MLLT10
(AF10)
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.
Atlas Genet Cytogenet Oncol Haematol. 2006;10(2)
Disease
M4 or M5 ANLL; ALL at times; therapy related
ANLL.
Prognosis
Poor
85
MLL (myeloid/lymphoid or mixed lineage leukemia)
Huret JL
• t(3;11)(q28;q23)/ANLL → MLL - LPP
• t(4;11)(p12;q23) → MLL - AF4p12
• t(4;11)(q12;q23) → MLL - MIFL
• t(4;11)(q21;q23)/atypical CML → MLL - SEPT11
• t(4;11)(q35;q23)→ MLL - ArgBP2
• t(5;11)(q31;q23)/ANLL, ALL → MLL - ARHGAP26
(GRAF)
• ins(5;11)(q31;q13q23)/ALL → MLL - AFF4
(AF5q31)
• t(6;11)(q12;q23)/ANLL → MLL - SMAP1
• t(6;11)(q21;q23)/ANLL → MLL - FOXO3A
(AF6q21)
• t(9;11)(q34;q23)/ANLL → MLL - DAB2IP
(AF9q34)
• t(10;11)(p11;q23)/ANLL → MLL - ABI1
• t(10;11)(q21;q23)/ANLL → MLL - CXXC6 (TET1)
• t(11;11)(q21;q23)/ANLL → MLL - PICALM
• trisomy 11/ANLL → MLL tandem duplication
• t(11;11)(q23;q23)/ANLL → MLL - CBL
• t(11;11)(q23;q23)/ANLL → MLL - ARHGEF12
(LARG)
• t(11;11)(q23;q24)/ANLL → MLL - TIRAP
• t(11;12)(q23;q13)/ANLL → MLL - CIP29
• t(11;14)(q23;q24)/ANLL, AUL → MLL - GPHN
• t(11;15)(q23;q14)/ANLL, ALL → MLL - CASC5
(AF15q14)
• t(11;15)(q23;q14) → MLL - MPFYVE
• t(11;15)(q23;q15) → MLL - AF15
• t(11;16)(q23;p13)/MDS, ANLL, t-ANLL, ALL →
MLL - CREBBP (CBP)
• t(11;17)(q23;p13)/t-ANLL → MLL - GAS7
• t(11;17)(q23;q21)/ANLL → MLL - ACACA
• t(11;17)(q23;q21)/ANLL → MLL - LASP1
• t(11;17)(q23;q21)/ANLL → MLL - MLLT6 (AF17)
• t(11;17)(q23;q21)/ANLL → MLL - RARa
• t(11;17)(q23;q25)/MDS, ANLL → MLL - SEPT9
(MSF1, AF17q25)
• t(11;19)(q23;p13)/ANLL → MLL - SH3GLI1 (EEN)
• t(11;19)(q23;p13)/ANLL → MLL - MYO1F
• t(11;20)(q23;q11)/ALL → MLL - MAPRE1 (EB1)
• t(11;22)(q23;q11.2)/ANLL → MLL - SEPT5
(hCDCRel)
• t(11;22)(q23;q13)/ANLL → MLL - EP300 (P300)
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-MLLT1 (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.
Other entities
• 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- EB15 (AF1p)
• t(1;11)(q21;q23)/ANLL → MLL- MLLT11 (AF1q)
• t(2;11)(q11;q23)/ALL → MLL- AFF3 (LAF4)
• t(3;11)(p21;q23)/t-ANLL, ALL→ MLL- NCKIPSD
(AF3p21)
• t(3;11)(q21;q23)/ALL → MLL- EEFSEC (SELB)
• t(3;11)(q25;q23)/t-ANLL → MLL - GMPS
Atlas Genet Cytogenet Oncol Haematol. 2006;10(2)
86
MLL (myeloid/lymphoid or mixed lineage leukemia)
Huret JL
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 MLLT1 (ENL), to near the COOH-term in MLLT3 (AF9).
To be noted
gene involved in translocations to chromosomal region 11q23
and acute leukaemias. Brit J Haematol 1996;93:966-972.
Note: the card on 11q23 rearrangements, gives an
overview on diseases implicating MLL, as well as
11q23 rearrangements in therapy related leukemias.
See also 11q23 rearrangements in childhood acute
lymphoblastic leukemia: Clinical aspects and
congenital leukemias.
Young BD, Saha V. Chromosome abnormalities in leukaemia:
the 11q23 paradigm. Cancer Surv 1996;28:225-245.
References
Waring PM, Cleary ML. Disruption of a Homolog of Trithorax
by 11q23 translocations: leukemogenic and transctiptional
implications. Current Topics Microbiol Immunol 1997;220:1-23.
Rubnitz JE, et al. 11q23 rearrangements in acute leukemia.
Leukemia 1996;10:74-82. (Review).
Prasad R, et al. Structure and expression pattern of human
ALR, a novel gene with strong homology to ALL-1 involved in
acute leukemia and to Drosophila trithorax. Oncogene
1997;15:549-560.
Schichman SA, Canaani E, Croce CM. Self-fusion of the ALL1
gene. A new genetic mechanism for acute leukemia. JAMA
1995;273:571-576.
DiMartino JF, Cleary ML. MLL rearrangements in
hematological malignancies: lessons from clinical and
biological studies. Br J Haemotol 1999;106:614-626.
Bernard OA, Berger R. Molecular basis of 11q23
rearrangements in hematopoietic malignant proliferations.
Genes Chromosom Cancer 1995;13:75-85.
Huntsman DG, et al. MLL2, the second homolog of the
Drosophila trithorax gene, maps to 19q13.1 and is amplified in
solid tumor lines. Oncogene 1999;18:7975-7984.
Rasio D, Schichman SA, Negrini M, Canaani E, Croce CM.
Complete exon structure of the ALL1 gene. Cancer Res
1996;56:1766-1769.
This article should be referenced as such:
Huret JL. MLL (myeloid/lymphoid or mixed lineage leukemia).
Atlas Genet Cytogenet Oncol Haematol.2006;10(2):83-87.
Nilson I, Löchner K, Siegler G, Greil J, Beck JD, Fey GH,
Marschalek R. Exon/intron structure of the human ALL-1 (MLL)
Atlas Genet Cytogenet Oncol Haematol. 2006;10(2)
87