Trends in Molecular Medicine
MLL: a histone methyltransferase disrupted in leukemia
Section snippets
The normal function of MLL
MLL is homologous to the trithorax (trx) gene in flies. MLL and trx are members of an evolutionarily conserved family of proteins, the trithorax group (trx-G), that positively regulate gene expression during development. These proteins were originally identified by studying mutant flies with altered segment identities called homeotic transformations. The disruptive effects of trx-G mutations can be rescued by mutations in the Polycomb group (Pc-G) genes, which ultimately led to the recognition
Mechanism of transcriptional regulation by MLL
By itself, MLLN has net repressive effects on transcription [17]. This might be mediated by the recruitment of the co-repressors CtBP and the Pc-G proteins (Hpc and Bmi) to the DNMT homology region of MLL 17, 22. In addition, histone deacetylases are also recruited by the DNMT region, a process that is enhanced by interaction with the protein cyp33, which binds to the PHD fingers of MLL [23]. However, when heterodimerized with MLLC, the complex has net activating effects on transcription (
MLL fusion proteins
Balanced translocations involving the MLL cluster between exons 8 and 12 result in the deletion of the PHD and distal domains and in-frame fusion to one of many different translocation partners (Figure 1). Presumably, the breaks are limited to this region in leukemias because more proximal or distal breaks are not compatible with transformation. These fusion proteins do not appear to interact with MLLC [17]. The reciprocal fusion product containing the N-terminal translocation partner and
Partial tandem duplication of MLL
About 10% of AML cases with normal cytogenetics (therefore lacking a translocation) harbor internal tandem duplications of MLL (Figure 1), an important finding because these cases are associated with a worse prognosis than those without MLL rearrangements [7]. Most of these cases occur in adults. This raises several unresolved issues. One is how the mechanism for transformation by this form of MLL is related to the activity of dimerized MLL. Data suggests that the crucial alteration is a
MLL amplification
For some cases of myelodysplastic syndrome (MDS) and AML, MLL is present in increased copy number. This occurs as the result of additional copies of chromosome 11 or through MLL amplification [8]. The coding region of MLL is apparently unaltered but overexpressed in these cases. The amplification of MLL is also associated with the upregulation of at least some of the genes that are consistently expressed in leukemias with MLL rearrangements, suggesting similar mechanisms of transformation.
Hox genes are crucial targets of leukemogenic forms of MLL
Although MLL fusion proteins affect the expression of many genes, the upregulation of Hox genes appears to be the most crucial for transformation. Hox genes, such as Hox a9, are important regulators of hematopoiesis and act, in part, by promoting stem-cell renewal 56, 57. The A cluster Hox genes, including Hox a7 and Hox a9 and the Hox cofactor Meis1, are normally only expressed in early hematopoietic stem cells; their expression is then rapidly downregulated [58]. Hox a7 and Hox a9 are
Concluding remarks
One possible target for MLL-directed therapy includes targeting the gain-of-function activity of the fusion protein itself, possibly by inhibiting yet to be identified posttranslational modifications of MLL or through inhibitors of the SWI–SNF ATPase (Figure 4). This strategy will depend on whether transformation by MLL is ‘hit and run’. One concern is that studies of long-term cultures of conditionally transformed murine cells [39] suggest that secondary hits occur that render cells MLL and Hox
Acknowledgements
I thank Dr. Robert Slany for critical reading of the manuscript. Many have contributed to the MLL field and I extend my apologies in advance to those whose work was not specifically cited because of space limitations. This work was supported in part from grants from the NIH and from the Lymphoma and Leukemia Society.
Glossary
- AF4:
- MLL translocation partner on chromosome 4q21
- AF9:
- MLL translocation partner on chromosome 9p22
- AFX:
- forkhead-related transcription factor, an MLL translocation partner on Xq13
- ALL:
- acute lymphoblastic leukemia, a clonal malignancy of lymphocyte progenitors
- AML:
- acute myeloid leukemia, a clonal malignancy of granulocyte progenitors
- AT hooks:
- evolutionarily conserved domain of MLL that binds to AT-rich DNA
- BRG-1:
- brahma-related gene 1, an SWI–SNF component with ATPase activity
- CBP:
- cAMP response-element
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