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PMID: 20541448 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Multiple interactions recruit MLL1 and MLL1 fusion proteins to the HOXA9 locus in leukemogenesis.

Molecular cell ·Vol. 38 ·No. 6 ·2010-06-25 ·Pages 853-63

Milne TA, Kim J, Wang GG, Stadler SC, Basrur V, Whitcomb SJ, Wang Z, Ruthenburg AJ, Elenitoba-Johnson KS, Roeder RG, Allis CD

Abstract

MLL1 fusion proteins activate HoxA9 gene expression and cause aggressive leukemias that respond poorly to treatment, but how they recognize and stably bind to HoxA9 is not clearly understood. In a systematic analysis of MLL1 domain recruitment activity, we identified an essential MLL1 recruitment domain that includes the CXXC domain and PHD fingers and is controlled by direct interactions with the PAF elongation complex and H3K4Me2/3. MLL1 fusion proteins lack the PHD fingers and require prebinding of a wild-type MLL1 complex and CXXC domain recognition of DNA for stable HoxA9 association. Together, these results suggest that specific recruitment of MLL1 requires multiple interactions and is a precondition for stable recruitment of MLL1 fusion proteins to HoxA9 in leukemogenesis. Since wild-type MLL1 and oncogenic MLL1 fusion proteins have overlapping yet distinct recruitment mechanisms, this creates a window of opportunity that could be exploited for the development of targeted therapies.

MeSH Terms
Animals Cell Line Genetic Loci Histone-Lysine N-Methyltransferase Homeodomain Proteins/genetics,metabolism Humans Leukemia/metabolism Mice Myeloid-Lymphoid Leukemia Protein/genetics,metabolism Nuclear Proteins/metabolism Oncogene Proteins, Fusion/metabolism Point Mutation Protein Structure, Tertiary Protein Transport Transcription Factors
Chemicals
Homeodomain Proteins MLL-AF9 fusion protein, mouse Nuclear Proteins Oncogene Proteins, Fusion PAF1 protein, human Transcription Factors homeobox protein HOXA9 Myeloid-Lymphoid Leukemia Protein Histone-Lysine N-Methyltransferase Kmt2a protein, mouse
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Milne Thomas A
Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065, USA.
Kim Jaehoon
Wang Gang G
Stadler Sonja C
Basrur Venkatesha
Whitcomb Sarah J
Wang Zhanxin
Ruthenburg Alexander J
Elenitoba-Johnson Kojo S J
Roeder Robert G
Allis C David
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Article Info
Journal
Molecular cell
Abbr.
Mol Cell
ISSN
1097-4164
DOI
10.1016/j.molcel.2010.05.011
Published
2010-06-25
Epub
2010-00-10
Pages
853-63
Language
English
Region
United States
NLM ID
9802571
PMCID
PMC2902588
Subset
IM
Grants
NCI NIH HHS · K99 CA151683 · United States
NIGMS NIH HHS · R37 GM053512 · United States
NIGMS NIH HHS · R37 GM053512-25 · United States
CIHR · Canada
Corrections
CommentIn
PMID: 20677349
External Links
PubMed source DOI: 10.1016/j.molcel.2010.05.011 PMC Full Text View journal details
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