International Journal of Hematology

, Volume 82, Issue 1, pp 9–20 | Cite as

Molecular Pathogenesis of MLL-Associated Leukemias

  • Mariko Eguchi
  • Minenori Eguchi-Ishimae
  • Mel Greaves


Chromosome translocations disrupting theMLL gene are associated with various hematologic malignancies but are particularly common in infant and secondary therapy-related acute leukemias. The normal MLL-encoded protein is an essential component of a supercomplex with chromatin-modulating activity conferred by histone acetylase and methyltransferase activities, and the protein plays a key role in the developmental regulation of gene expression, includingHox gene expression. In leukemia, this function is subverted by breakage, recombination, and the formation of chimeric fusion with one of many alternative partners. SuchMLL translocations result in the replacement of the C-terminal functional domains of MLL with those of a fusion partner, yielding a newly formed MLL chimeric protein with an altered function that endows hematopoietic progenitors with self-renewing and leukemogenic activity. This potent impact of the MLL chimera can be attributed to one of 2 kinds of activity of the fusion partner: direct transcriptional transactivation or dimerization/oligomerization. Key unresolved issues currently being addressed include the set of target genes forMLL fusions, the stem cell of origin for the leukemias, the role of additional secondary mutations, and the origins or etiology of theMLL gene fusions themselves. Further elaboration of the biology ofMLL gene-associated leukemia should lead to novel and specific therapeutic strategies.

Key words

MLL gene Histone methylation/acetylation Hematopoietic stem cells Mouse models Short latency 


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Copyright information

© The Japanese Society of Hematology 2005

Authors and Affiliations

  • Mariko Eguchi
    • 1
  • Minenori Eguchi-Ishimae
    • 1
  • Mel Greaves
    • 1
  1. 1.Section of Haemato-Oncology, Institute of Cancer ResearchChester Beatty LaboratoriesLondonUK

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