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Cancer Cell. 2014 Dec 8;26(6):896-908. doi: 10.1016/j.ccell.2014.10.009. Epub 2014 Nov 20.

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

Author information

1
Division of Hematology/Oncology, Children's Hospital Boston, Boston, MA 02115, USA; Department of Pediatrics and the Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
2
Department of Pediatrics and the Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
3
Division of Hematology/Oncology, Children's Hospital Boston, Boston, MA 02115, USA.
4
Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, NY 10065, USA.
5
Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
6
Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
7
Department of Pediatrics, University of Colorado Anshutz Medical Campus, Aurora, CO 80045 USA.
8
Division of Hematology/Oncology, Children's Hospital Boston, Boston, MA 02115, USA; Department of Pediatrics and the Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: armstros@mskcc.org.

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.

PMID:
25464900
PMCID:
PMC4291116
DOI:
10.1016/j.ccell.2014.10.009
[Indexed for MEDLINE]
Free PMC Article

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