Mutations in DNA methyltransferase 3A (DNMT3A) are common in acute myeloid leukemia (AML) patients, and unfortunately, carriers of this particular gene mutation generally have a poor prognosis. And although scholars don’t fully understand the exact mechanisms by which DNMT3A loss contributes to leukemogenesis, murine stem cell research, as described in an August 2016 article published by Rau, et al in The American Society of Hematology’s journal, Blood, has shown that when DNMT3A is deleted or suppressed, histone 2 lysine (H3K79) mythltransferase, DOT1L is overexpressed.


This finding led the team of Texas based researchers to investigate DOT1L as a therapeutic target for the treatment of DNMT3A-mutant AML, and the results were very promising. Using a nude rat xenograft model of DNMT3A-mutant AML that was subcutaneously injected with OCI AML3 cells, Rau et al were able to engraft a leukemic tumor. The xenograft model showed in vivio efficacy of a pharmacologic DOT1L inhibitor. The in vivio findings, which were consistent with in vitro results, showed that when nude rat xenograft models were treated with continuous IV of EPZ-5676, a DOT1L inhibitor currently being tested in phase 1 clinical trials for patients with mixed-lineage leukemia (MLL), tumor growth was effectively suppressed. Additionally, these in vivio studies showed that inhibition of DOT1L also reduced colony-forming capacity (CFC) and induced terminal differentiation in vitro – all signs that suggest that DOT1L may play an even more critical role in AML than previously understood.


Based on the observations from the DNMT3A-mutant AML rat model described above, there is significant preclinical rational for clinical investigation of pharmacologic DOT1L inhibitors for DNMT3A-mutant leukemia (AML). Ultimately, if these results are validated, DOT1L inhibitors could provide unprecedented therapeutic treatments for a group of AML patients who have traditionally had an exceptionally poor prognosis.