MLL
MIM.159555 11q23
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The MLL gene is homologous to Drosophila trithorax and is likewise involved in embryo pattern formation.
Translocations that involve the mixed lineage leukaemia (MLL) gene identify a unique group of acute leukaemias, and often predict a poor prognosis.
The MLL gene encodes a DNA-binding protein that methylates histone H3 lysine 4 (H3K4), and positively regulates gene expression including multiple Hox genes.
Leukaemogenic MLL translocations encode MLL fusion proteins that have lost H3K4 methyltransferase activity.
A key feature of MLL fusion proteins is their ability to efficiently transform haematopoietic cells into leukaemia stem cells. The link between a chromatin modulator and leukaemia stem cells provides support for epigenetic landscapes as an important part of leukaemia and normal stem-cell development.
Trithorax (MLL) imprints
Trimethylation of Lys 4 on histone H3 correlates with transcriptional activity, and MLL1 was recently shown to be a histone H3 Lys 4-specific methyltransferase.
MLL1 has been found to associate with other epigenetic regulators, such as the HAT CBP and INI1, a subunit of the SWI/SNF nucleosome remodeling complex, and one study found MLL1 to reside in a large protein assembly containing subunits capable of regulating transcription preinitiation, nucleosome remodeling, histone acetylation, and histone methylation.
A similarly orchestrated epigenetic regulation was demonstrated for the Drosophila Trithorax-like protein Ash1, a histone methyltransferase (HMT) capable of methylating Lys 4 and Lys 9 of histone H3 and Lys 20 on histone H4.
The Ash1-specific methylation imprint was found to displace HP1 and PcG proteins, which are normally bound to repressed genes, and instead facilitates the binding of the Brahma chromatin remodeling complex.
Interestingly, recent data from Drosophila studies indicate that TrxG proteins such as Trx and Ash1, rather than being general transcriptional coactivators, specifically function to prevent inappropriate silencing mediated by the PcG of transcriptional repressors (Klymenko and Muller 2004).
Pathology
Myeloid/lymphoid leukemia (MLL) gene rearrangements are high risk cytogenetic characteristics of acute lymphoblastic leukemia (ALL).
Myeloid/lymphoid leukemia (MLL) gene rearrangements are signs of a bad prognosis in childhood acute lymphoblastic leukemia (ALL). This gene has an important role in developmental regulation of gene expression in normal hematopoiesis.
The MLL gene is located on the 11q23 chromosomal region. Translocations are the most common rearrangements detected, while deletions are rarely seen. Some publications have reported that MLL gene deletions were predominantly at the 3′ end and were accompanied by a MLL translocation that had the major role in the designation of the prognosis. However, it is not easy to predict the prognostic effect of the 3′ deletion of the MLL gene without a translocation. Rare publications have reported finding a 5′ deletion of the MLL gene.
MLL fusion genes are a predominant feature of acute leukemias in infants and in secondary acute myeloid leukemia (AML) associated with prior chemotherapy with topo-II poisons.
Acute leukemias in infants are considered to possibly arise in utero via transplacental chemical exposure. A striking feature of these leukemias is their malignancy and remarkably brief latencies implying the rapid acquisition of any necessary additional mutations.
chromosomal translocations involving the mixed lineage leukemia gene (MLL) located at 11q23 in
- acute lymphoblastic leukemia (ALL)
- acute myeloid leukemia (AML)
| MLL-GMPS | |||
| MLL-MLLT2 | t(4;11)(q21;q23) | 4q21 and 11q23 | |
| MLL-FNBP1 | ins(11;9)(q23;134)inv(11)(q13q23) | acute myeloid leukemia | |
| MLL-LPP | |||
| MLL-GPH | t(11;14)(q23;q24) | 11q23 and 14q24 | acute undifferentiated leukemia |
| MLL-PNUTL1 | t(11;22)(q23;q11) | 11q23 and 22q11 | acute myeloid leukemia |
| MLL-CDK6 | |||
| MLL-LASP1 | |||
| MLL-GRAF | |||
| MLL-ABI1 | |||
| MLL-LAF4 | ins(11;2)(q23;q11) | 2q11 and 11q23 | acute lymphoblastic leukemia |
| MLL-CBL | - | acute myeloid leukemia | |
| MLL-LARG | |||
| MLL-AF9 | t(9;11)(p22;q23) | acute myeloid leukemia | |
| MLL-CALM | - | infant acute myeloid leukemia | |
| MLL-SH3GL1 | t(11;19)(q23;p13.3) | acute myeloid leukemia | |
| MLL-FOXO3A | t(6;11)(q21;q23) | secondary acute myeloblastic leukemia | #9345057# |
| MLL-AF17 | t(11;17)(q23;q12-q21) | acute myelocytic leukemia | #15676155# |
| MLL-CT45A2 | rearr. Xq26.3 - 11q23 | pediatric biphenotypic acute leukemia | #20920256# |
And
MLL/MLLT1 by t(11;19)(q23;p13) in acute mixed lineage leukemias (11q23 and 19p13)
MLL/MLLT2 (AF4) by t(4;11)(q21;q23) in acute mixed lineage leukemias (4q21 and 11q23)
MLL/MLLT3 (AF9) fusion gene by t(9;11)(p22;q23) in ANLL (acute myeloid leukemia) (9p22 and 11q23)
MLL/MLLT4 (AF6) fusion gene by t(6;11)(q27;q23) in ANLL (acute myeloid leukemia) (6q27 and 11q23)
MLL/MLLT7 (AFX1) fusion gene by t(X;11)(q13;q23) in ANLL (acute myeloid leukemia) (Xq13 and 11q23)
MLL/MLLT10 (AF10) fusion gene by t(10;11)(p12;q23) (9p22 and 11q23) (10p12 - MLL/MLLT6 (AF17) fusion gene by t(11;17)(q23;q21) in ANLL (acute myeloid leukemia) (6q27 and 11q23)and 11q23)
MLL/SEPT9 fusion gene by t(11;17)(q23;q25) in de novo myelodysplastic syndrome (#17250889#)
More than 40 specific translocations involving MLL1 have been described in human cancers. All fusion proteins retain the N-terminal part of MLL1, whereas the C-terminal part encoding the SET domain is lost.
The oncogenic capacity of several MLL fusion proteins has been verified in transgenic mice (Corral et al. 1996; Dobson et al. 1999). Mll heterozygous mice do not appear tumor prone, making haploinsufficiency a less likely cause of leukemogenesis (Corral et al. 1996).
Rather, the fusion proteins appear to exert dominant-negative functions over wild-type MLL (Arakawa et al. 1998; Ayton and Cleary 2001).
It remains enigmatic how MLL fusion proteins retain transcription activation capacity while lacking a functional SET domain and how structurally divergent fusion partners of MLL1 can result in relatively similar consequences in terms of cellular transformation. Recent data have demonstrated that dimerization of the MLL fusion partners may be an important virtue in some translocations (So et al. 2003).
This could explain the diversity in MLL fusion partners, but leaves open the question of which targets are selectively being (de)regulated by the MLL fusion proteins as compared with the wild-type MLL.
Intriguingly, the known MLL target genes HoxA7 and HoxA9 are both required for leukemia induction by an MLL fusion oncogene (Ayton and Cleary 2003).
In other MLL translocation products, the fusion partner moiety is likely capable of sequestering coactivators or nucleosome remodeling factors contributing to oncogenesis.
The numerous translocations involving MLL1 likely promotes leukemia through messing up epigenetic codes.
See also
MLL-associated leukemias
Free references
Lund AH, van Lohuizen M. Epigenetics and cancer. Genes Dev. 2004 Oct 1;18(19):2315-35. PMID: #15466484#
Reviews
Collins EC, Rabbitts TH. The promiscuous MLL gene links chromosomal translocations to cellular differentiation and tumour tropism. Trends Mol Med. 2002 Sep;8(9):436-42. PMID: #12223315#
Gerasimova, T. I., and V. G. Corces. 1998. Polycomb and Trithorax group proteins mediate the function of a chromatin insulator. Cell 92:511-521.
References
Krivtsov AV, Armstrong SA. MLL translocations, histone modifications and leukaemia stem-cell development. Nat Rev Cancer. 2007 Nov;7(11):823-33. PMID: #17957188#
Kreuziger LM, Porcher JC, Ketterling RP, Steensma DP. An MLL-SEPT9 fusion and t(11;17)(q23;q25) associated with de novo myelodysplastic syndrome. Leuk Res. 2007 Aug;31(8):1153-6. PMID: #17250889#
Eguchi M, Eguchi-Ishimae M, Knight D, Kearney L, Slany R, Greaves M. MLL chimeric protein activation renders cells vulnerable to chromosomal damage: an explanation for the very short latency of infant leukemia. Genes Chromosomes Cancer. 2006 Aug;45(8):754-60. PMID: #16688745#