| Literature DB >> 25464900 |
Aniruddha J Deshpande1, Anagha Deshpande2, Amit U Sinha2, Liying Chen3, Jenny Chang2, Ali Cihan4, Maurizio Fazio2, Chun-Wei Chen2, Nan Zhu2, Richard Koche2, Liuda Dzhekieva5, Gloria Ibáñez5, Stuart Dias3, Deepti Banka3, Andrei Krivtsov2, Minkui Luo5, Robert G Roeder4, James E Bradner6, Kathrin M Bernt7, Scott A Armstrong8.
Abstract
Homeotic (HOX) genes are dysregulated in multiple malignancies, including several AML subtypes. We demonstrate that H3K79 dimethylation (H3K79me2) is converted to monomethylation (H3K79me1) at HOX loci as hematopoietic cells mature, thus coinciding with a decrease in HOX gene expression. We show that H3K79 methyltransferase activity as well as H3K79me1-to-H3K79me2 conversion is regulated by the DOT1L cofactor AF10. AF10 inactivation reverses leukemia-associated epigenetic profiles, precludes abnormal HOXA gene expression, and impairs the transforming ability of MLL-AF9, MLL-AF6, and NUP98-NSD1 fusions-mechanistically distinct HOX-activating oncogenes. Furthermore, NUP98-NSD1-transformed cells are sensitive to small-molecule inhibition of DOT1L. Our findings demonstrate that pharmacological inhibition of the DOT1L/AF10 complex may provide therapeutic benefits in an array of malignancies with abnormal HOXA gene expression.Entities:
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Year: 2014 PMID： 25464900 PMCID： PMC4291116 DOI： 10.1016/j.ccell.2014.10.009
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743