AF10 regulates progressive H3K79 methylation and HOX gene expression in diverse AML subtypes. Cancer Cell 2014 Dec 08;26(6):896-908
Date
12/04/2014Pubmed ID
25464900Pubmed Central ID
PMC4291116DOI
10.1016/j.ccell.2014.10.009Scopus ID
2-s2.0-84919489217 (requires institutional sign-in at Scopus site) 148 CitationsAbstract
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.
Author List
Deshpande AJ, Deshpande A, Sinha AU, Chen L, Chang J, Cihan A, Fazio M, Chen CW, Zhu N, Koche R, Dzhekieva L, Ibáñez G, Dias S, Banka D, Krivtsov A, Luo M, Roeder RG, Bradner JE, Bernt KM, Armstrong SAMESH terms used to index this publication - Major topics in bold
AdenosineAnimals
Bone Marrow Cells
Epigenesis, Genetic
Gene Expression Regulation, Neoplastic
HL-60 Cells
Histones
Homeodomain Proteins
Humans
Leukemia, Myeloid, Acute
Methylation
Methyltransferases
Mice
Mice, Transgenic
Molecular Sequence Data
Neoplasms, Experimental
Nuclear Pore Complex Proteins
Nuclear Proteins
Oncogene Proteins, Fusion
Phenylurea Compounds
Transcription Factors
