• Major finding: Aberrant epigenetic activity of the histone methyltransferase DOT1L causes MLL.

  • Impact: A selective inhibitor of DOT1L prevents expression of leukemogenic genes and increases survival in a mouse model of MLL.

  • Significance: Small molecule inhibition of histone methyltransferases may be a potential therapeutic option for diseases caused by aberrant epigenetic activity.

Mixed lineage leukemia (MLL) is an aggressive form of leukemia that affects both infants and adults and typically carries a poor prognosis. The underlying genetic defect is a chromosomal translocation that fuses the MLL gene to a variety of partners, and the resulting oncogenic fusion proteins gain the ability to interact with at least 3 known protein complexes, one of which contains DOT1L, a histone methyltransferase that catalyzes the methylation of histone H3 (H3K79). The new association between DOT1L and the MLL fusion proteins results in DOT1L recruitment to aberrant gene locations. Previous studies of MLL-translocated leukemia have found enhancement of H3K79 methylation at MLL-fusion loci and hypothesized that DOT1L activity may activate and maintain MLL fusion-mediated gene expression. However, it remains unclear whether an epigenetic modification can regulate the transcription of a specific subset of leukemogenic genes. In a recent article, Bernt and colleagues investigated whether MLL fusion-mediated gene expression and leukemia maintenance depend on DOT1L. Using MLL-rearranged leukemia cells, the authors first identified MLL-fusion target loci and found them to be specifically associated with methylation of H3K79. Loss of Dot1l resulted in loss of H3K79 methylation, downregulation of MLL fusion target genes, and increased differentiation and apoptosis of leukemia cells. Dot1l also was necessary for the development of leukemia in vivo. Importantly, the discovery that the development and maintenance of MLL-rearranged leukemia is dependent upon a DOT1L-imposed aberrant epigenetic program suggests that DOT1L may be a potential therapeutic target for this disease. In a related article, Daigle and colleagues report the development of EPZ004777, a potent, selective inhibitor of DOT1L. Designed to sit in the catalytic active site of DOT1L, EPZ004777 specifically inhibited cellular H3K79 methylation, expression of MLL-fusion target genes, and proliferation of MLL-rearranged cells without affecting the proliferation of nontranslocated cells. In a mouse xenograft model of MLL, administration of EPZ004777 led to an overall increase in survival in the absence of overt toxicity or severe hematopoietic side effects. Overall, these results provide strong evidence that small molecule inhibition of DOT1L represents a potential targeted therapeutic against MLL-translocated leukemia, a disease that currently has limited treatment options.

Daigle S, Olhava EJ, Therkelsen CA, Majer CR, Sneeringer CJ, Song J, et al. Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor. Cancer Cell 2011;20:53–65.

Bernt KM, Zhu N, Sinha AU, Vempati S, Faber J, Krivtsov AV, et al. MLL-Rearranged leukemia is dependent on aberrant H3K79 methylation by DOT1L. Cancer Cell 2011;20:66–78.

Note:Research Watch is written by Cancer Discovery Editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.