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| 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 N-term 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. |
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| Expression | wide; especially in: brain, kidney, thyroid; expressed in Taned B lymphocytes and myeloid cells |
| Localisation | nuclear, in punctate spots |
| Function | transcriptional regulatory factor; MLL may have yin-yang functions through 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). |
| Homology | trithorax (Drosophila), ALR (human), MLL2 (human) |
| Entity | t(4;11)(q21;q23)/acute leukaemias --> MLL-AFF1 (AF4) |
| 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; 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 |
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| Entity | t(6;11)(q27;q23) /ANLL -->MLL- MLLT4 (AF6) |
| Disease | M5/M4 de novo and therapy related ANLL, T-cell ALL |
| Prognosis | poor |
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| Entity | t(9;11) (p22;q23)/ANLL -->MLL-MLLT3 (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 example) |
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| Entity | t(10;11)(p12;q23) /ANLL --> MLL- MLLT10 (AF10) |
| Disease | M4 or M5 ANLL; ALL at times; therapy related ANLL |
| Prognosis | poor |
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| Entity | 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 |
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| Entity | 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 |
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| Entity | 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
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) |
| | |
| Self-fusion of the ALL1 gene. A new genetic mechanism for acute leukemia. |
| Schichman SA, Canaani E, Croce CM |
| JAMA : the journal of the American Medical Association. 1995 ; 273 (7) : 571-576. |
| PMID 7837391 |
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| Molecular basis of 11q23 rearrangements in hematopoietic malignant proliferations. |
| Bernard OA, Berger R |
| Genes, chromosomes & cancer. 1995 ; 13 (2) : 75-85. |
| PMID 7542910 |
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| Complete exon structure of the ALL1 gene. |
| Rasio D, Schichman SA, Negrini M, Canaani E, Croce CM |
| Cancer research. 1996 ; 56 (8) : 1766-1769. |
| PMID 8620491 |
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| Exon/intron structure of the human ALL-1 (MLL) gene involved in translocations to chromosomal region 11q23 and acute leukaemias. |
| Nilson I, Lchner K, Siegler G, Greil J, Beck JD, Fey GH, Marschalek R |
| British journal of haematology. 1996 ; 93 (4) : 966-972. |
| PMID 8703835 |
| |
| Chromosome abnormalities in leukaemia: the 11q23 paradigm. |
| Young BD, Saha V |
| Cancer surveys. 1996 ; 28 : 225-245. |
| PMID 8977038 |
| |
| 11q23 rearrangements in acute leukemia. |
| Rubnitz JE, Behm FG, Downing JR |
| Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 1996 ; 10 (1) : 74-82. |
| PMID 8558942 |
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| Structure and expression pattern of human ALR, a novel gene with strong homology to ALL-1 involved in acute leukemia and to Drosophila trithorax. |
| Prasad R, Zhadanov AB, Sedkov Y, Bullrich F, Druck T, Rallapalli R, Yano T, Alder H, Croce CM, Huebner K, Mazo A, Canaani E |
| Oncogene. 1997 ; 15 (5) : 549-560. |
| PMID 9247308 |
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| Disruption of a homolog of trithorax by 11q23 translocations: leukemogenic and transcriptional implications. |
| Waring PM, Cleary ML |
| Current topics in microbiology and immunology. 1997 ; 220 : 1-23. |
| PMID 9103672 |
| |
| Mll rearrangements in haematological malignancies: lessons from clinical and biological studies. |
| Dimartino JF, Cleary ML |
| British journal of haematology. 1999 ; 106 (3) : 614-626. |
| PMID 10468849 |
| |
| MLL2, the second human homolog of the Drosophila trithorax gene, maps to 19q13.1 and is amplified in solid tumor cell lines. |
| Huntsman DG, Chin SF, Muleris M, Batley SJ, Collins VP, Wiedemann LM, Aparicio S, Caldas C |
| Oncogene. 1999 ; 18 (56) : 7975-7984. |
| PMID 10637508 |
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| Written | 12-1997 | Jean-Loup Huret |
| | Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France |
| Updated | 12-2000 | Jay L Hess, Jean-Loup Huret |
| | Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France |
| Updated | 11-2002 | Rolf Marschalek |
| | Instituts fĂźr Pharmazeutische Biologie, JWG Universitaet Frankfurt/Main, Biozentrum, N230, 303, Marie Curie Str. 9, D-60439 Frankfurt/Main, Germany |
| Updated | 10-2005 | Jean-Loup Huret |
| | Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France |
