alexa Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor.
Genetics & Molecular Biology

Genetics & Molecular Biology

Journal of Molecular Biomarkers & Diagnosis

Author(s): Daigle SR, Olhava EJ, Therkelsen CA, Majer CR, Sneeringer CJ,

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Abstract Mislocated enzymatic activity of DOT1L has been proposed as a driver of leukemogenesis in mixed lineage leukemia (MLL). The characterization of EPZ004777, a potent, selective inhibitor of DOT1L is reported. Treatment of MLL cells with the compound selectively inhibits H3K79 methylation and blocks expression of leukemogenic genes. Exposure of leukemic cells to EPZ004777 results in selective killing of those cells bearing the MLL gene translocation, with little effect on non-MLL-translocated cells. Finally, in vivo administration of EPZ004777 leads to extension of survival in a mouse MLL xenograft model. These results provide compelling support for DOT1L inhibition as a basis for targeted therapeutics against MLL. Copyright © 2011 Elsevier Inc. All rights reserved.
This article was published in Cancer Cell and referenced in Journal of Molecular Biomarkers & Diagnosis

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