TARGETING THE EPIGENETIC LESION IN MLL-REARRANGED LEUKEMIA

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It has become increasingly apparent that the misregulation of histone modification actively contributes to cancer. The histone H3 lysine 79 (H3K79) methyltransferase Dot1l has been implicated in the development of leukemias bearing translocations of the Mixed Lineage Leukemia (MLL) gene. We studied the global epigenetic profile for H3K79 dimethylation and found abnormal H3K79 dimethylation profiles exist not only in leukemias driven by MLL-fusion proteins with nuclear partners like AF9, but also in leukemia with MLL-fusions containing cytoplasmic partners like AF6. Genetic inactivation of Dot1l led to downregulation of fusion target genes and impaired both in vitro bone marrow transformation and in vivo leukemia development by MLL-AF10, CALM-AF10 as well as MLL-AF6, suggesting that aberrant H3K79 methylation by DOT1L sustains fusion-target gene expression in MLL rearranged leukemias and CALM-AF10 rearranged leukemias. Pharmacological inhibition of DOT1L selectively killed MLL-AF10 and MLL-AF6 transformed cells but not Hox9/Meis1 transformed cells, pointing to DOT1L as a potential therapeutic target in MLL-rearranged leukemia.