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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / analogs & derivatives
  • Adenosine / pharmacology
  • Animals
  • Bone Marrow Cells / metabolism
  • Epigenesis, Genetic
  • Gene Expression Regulation, Neoplastic / drug effects
  • HL-60 Cells
  • Histones / metabolism*
  • Homeodomain Proteins / metabolism*
  • Humans
  • Leukemia, Myeloid, Acute / metabolism*
  • Leukemia, Myeloid, Acute / pathology*
  • Methylation
  • Methyltransferases / antagonists & inhibitors
  • Methyltransferases / metabolism*
  • Mice
  • Mice, Transgenic
  • Molecular Sequence Data
  • Neoplasms, Experimental
  • Nuclear Pore Complex Proteins / metabolism
  • Nuclear Proteins / metabolism
  • Oncogene Proteins, Fusion / metabolism
  • Phenylurea Compounds / pharmacology
  • Transcription Factors / metabolism*

Substances

  • EPZ004777
  • Histones
  • Homeodomain Proteins
  • Nuclear Pore Complex Proteins
  • Nuclear Proteins
  • Oncogene Proteins, Fusion
  • Phenylurea Compounds
  • Transcription Factors
  • nuclear pore complex protein 98
  • Methyltransferases
  • Adenosine

Associated data

  • GEO/GSE54500