AF10 regulates progressive H3K79 methylation and HOX gene expression in diverse AML subtypes Journal Article

   

Authors:	Deshpande, A. J.; Deshpande, A.; Sinha, A. U.; Chen, L.; Chang, J.; Cihan, A.; Fazio, M.; Chen, C. W.; Zhu, N.; Koche, R.; Dzhekieva, L.; Ibáñez, G.; Dias, S.; Banka, D.; Krivtsov, A.; Luo, M.; Roeder, R. G.; Bradner, J. E.; Bernt, K. M.; Armstrong, S. A.
Article Title:	AF10 regulates progressive H3K79 methylation and HOX gene expression in diverse AML subtypes
Abstract:	Homeotic (. HOX) genes are dysregulated in multiple malignancies, including several AML subtypes. Wedemonstrate that H3K79 dimethylation (H3K79me2) is converted to monomethylation (H3K79me1) at. HOXloci as hematopoietic cells mature, thus coinciding with a decrease in HOX gene expression. Weshow 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.
Journal Title:	Cancer Cell
Volume:	26
Issue:	6
ISSN:	1535-6108
Publisher:	Cell Press
Date Published:	2014-12-08
Start Page:	896
End Page:	908
Language:	English
DOI:	10.1016/j.ccell.2014.10.009
PROVIDER:	scopus
PUBMED:	25464900
PMCID:	PMC4291116
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-84919489217&partnerID=40&md5=867e26414ebd0b1e79a27ccae610f5db
Notes:	Export Date: 2 January 2015 -- Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/65752