AF10 Regulates Progressive H3K79 Methylation and HOX Gene Expression in Diverse AML Subtypes
Copyright policy )AF10 Regulates Progressive H3K79 Methylation and HOX Gene Expression in Diverse AML Subtypes
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.
- Boston Children's Hospital United States
- University of Colorado System United States
- University of Colorado Boulder United States
- Harvard University United States
- Dana-Farber Cancer Institute United States
Homeodomain Proteins, Cancer Research, Adenosine, Oncogene Proteins, Fusion, Phenylurea Compounds, Molecular Sequence Data, Nuclear Proteins, Bone Marrow Cells, HL-60 Cells, Mice, Transgenic, Cell Biology, Methyltransferases, Neoplasms, Experimental, Methylation, Epigenesis, Genetic, Gene Expression Regulation, Neoplastic, Histones, Nuclear Pore Complex Proteins, Leukemia, Myeloid, Acute, Mice, Oncology, Animals, Humans
Homeodomain Proteins, Cancer Research, Adenosine, Oncogene Proteins, Fusion, Phenylurea Compounds, Molecular Sequence Data, Nuclear Proteins, Bone Marrow Cells, HL-60 Cells, Mice, Transgenic, Cell Biology, Methyltransferases, Neoplasms, Experimental, Methylation, Epigenesis, Genetic, Gene Expression Regulation, Neoplastic, Histones, Nuclear Pore Complex Proteins, Leukemia, Myeloid, Acute, Mice, Oncology, Animals, Humans
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