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PMID: 16105754 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Review

Molecular pathogenesis of MLL-associated leukemias.

International journal of hematology ·Vol. 82 ·No. 1 ·2005-07-00 ·Pages 9-20

Eguchi M, Eguchi-Ishimae M, Greaves M

Abstract

Chromosome translocations disrupting the MLL 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, including Hox gene expression. In leukemia, this function is subverted by breakage, recombination, and the formation of chimeric fusion with one of many alternative partners. Such MLL 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 for MLL fusions, the stem cell of origin for the leukemias, the role of additional secondary mutations, and the origins or etiology of the MLL gene fusions themselves. Further elaboration of the biology of MLL gene-associated leukemia should lead to novel and specific therapeutic strategies.

MeSH Terms
Acute Disease Hematopoiesis/physiology Hematopoietic Stem Cells/physiology Histone-Lysine N-Methyltransferase Humans Leukemia/genetics,physiopathology Myeloid-Lymphoid Leukemia Protein/genetics,physiology Oncogene Proteins, Fusion/physiology Translocation, Genetic
Chemicals
KMT2A protein, human Oncogene Proteins, Fusion Myeloid-Lymphoid Leukemia Protein Histone-Lysine N-Methyltransferase
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Eguchi Mariko
Section of Haemato-Oncology, Institute of Cancer Research, London, UK. mariko.eguchi@icr.ac.uk
Eguchi-Ishimae Minenori
Greaves Mel
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Article Info
Journal
International journal of hematology
Abbr.
Int J Hematol
ISSN
0925-5710
DOI
10.1532/IJH97.05042
Email
mariko.eguchi@icr.ac.uk
Published
2005-07-00
Pages
9-20
Language
English
Region
Japan
NLM ID
9111627
Subset
IM
External Links
PubMed source DOI: 10.1532/IJH97.05042 View journal details
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