| Multiple interactions recruit MLL1 and MLL1 fusion proteins to the HOXA9 locus in leukemogenesis. | |
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MedLine Citation:
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PMID: 20541448 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Thomas A Milne; Jaehoon Kim; Gang G Wang; Sonja C Stadler; Venkatesha Basrur; Sarah J Whitcomb; Zhanxin Wang; Alexander J Ruthenburg; Kojo S J Elenitoba-Johnson; Robert G Roeder; C David Allis |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-06-10 |
Journal Detail:
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Title: Molecular cell Volume: 38 ISSN: 1097-4164 ISO Abbreviation: Mol. Cell Publication Date: 2010 Jun |
Date Detail:
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Created Date: 2010-07-12 Completed Date: 2010-08-10 Revised Date: 2011-08-01 |
Medline Journal Info:
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Nlm Unique ID: 9802571 Medline TA: Mol Cell Country: United States |
Other Details:
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Languages: eng Pagination: 853-63 Citation Subset: IM |
Copyright Information:
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Copyright (c) 2010 Elsevier Inc. All rights reserved. |
Affiliation:
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Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cell Line Genetic Loci 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 |
| Grant Support | |
ID/Acronym/Agency:
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R37 GM053512-25/GM/NIGMS NIH HHS; //Canadian Institutes of Health Research |
| Chemical | |
Reg. No./Substance:
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0/Homeodomain Proteins; 0/MLL-AF9 fusion protein, mouse; 0/Mll protein, mouse; 0/Nuclear Proteins; 0/Oncogene Proteins, Fusion; 0/PAF1 protein, human; 0/homeobox protein HOXA9; 149025-06-9/Myeloid-Lymphoid Leukemia Protein |
| Comments/Corrections | |
Comment In:
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Nat Rev Cancer. 2010 Aug;10(8):529
[PMID:
20677349
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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