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23361907
Leukemic transformation by the MLL-AF6 fusion oncogene requires the H3K79 methyltransferase Dot1l.

Blood, 2013/3/28;121(13):2533-41.

Deshpande AJ[1], Chen L, Fazio M, Sinha AU, Bernt KM, Banka D, Dias S, Chang J, Olhava EJ, Daigle SR, Richon VM, Pollock RM, Armstrong SA

Affiliations

PMID: 23361907DOI: 10.1182/blood-2012-11-465120

Impact factor: 25.476

Abstract
The t(6;11)(q27;q23) is a recurrent chromosomal rearrangement that encodes the MLLAF6 fusion oncoprotein and is observed in patients with diverse hematologic malignancies. The presence of the t(6;11)(q27;q23) has been linked to poor overall survival in patients with AML. In this study, we demonstrate that MLL-AF6 requires continued activity of the histone-methyltransferase DOT1L to maintain expression of the MLL-AF6-driven oncogenic gene-expression program. Using gene-expression analysis and genome-wide chromatin immunoprecipitation studies followed by next generation sequencing, we found that MLL-fusion target genes display markedly high levels of histone 3 at lysine 79 (H3K79) dimethylation in murine MLL-AF6 leukemias as well as in ML2, a human myelomonocytic leukemia cell line bearing the t(6;11)(q27;q23) translocation. Targeted disruption of Dot1l using a conditional knockout mouse model inhibited leukemogenesis mediated by the MLL-AF6 fusion oncogene. Moreover, both murine MLL-AF6-transformed cells as well as the human MLL-AF6-positive ML2 leukemia cell line displayed specific sensitivity to EPZ0004777, a recently described, selective, small-molecule inhibitor of Dot1l. Dot1l inhibition resulted in significantly decreased proliferation, decreased expression of MLL-AF6 target genes, and cell cycle arrest of MLL-AF6-transformed cells. These results indicate that patients bearing the t(6;11)(q27;q23) translocation may benefit from therapeutic agents targeting aberrant H3K79 methylation.
MeSH terms
Adenosine; Animals; Cell Proliferation; Cell Transformation, Neoplastic; Cells, Cultured; Enzyme Inhibitors; Histone Methyltransferases; Histone-Lysine N-Methyltransferase; Kinesins; Lysine; Methyltransferases; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Biological; Myeloid-Lymphoid Leukemia Protein; Myosins; Oncogene Proteins, Fusion; Phenylurea Compounds
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