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Genetic alterations of the mixed-lineage leukemia (MLL) gene are commonly implicated in the development of acute leukemias. In acute myeloid leukemia (AML) a partial tandem duplication (PTD) of MLL occurs in about 5%–11%1–4 of patients and has been linked to poor treatment outcome.1,5 Although recent studies show that MLL-PTD does not have a prognostic impact in CN-AML patients treated with intensive therapy,2,3 many patients still succumb to their disease,2,3,5–7 and the course of disease for patients not eligible for intensive chemotherapy is even more dismal. Thus, novel and innovative treatment approaches are needed. In acute leukemias, the MLL gene is also commonly affected by chromosomal rearrangements. Several MLL-rearranged leukemias were recently shown to be dependent on the only known histone 3 lysine 79 (H3K79) methyltransferase DOT1L.8,9 Genetic deletion of DOT1L impairs initiation and maintenance of MLL-rearranged leukemias in mouse models8–12 and pharmacological inhibition of DOT1L with the specific small molecules EPZ004777 or EPZ-5676 selectively kills MLL-rearranged leukemia cells in vitro13 and in vivo.14 Furthermore, DOT1L inhibition leads to a reversal of a characteristic gene expression signature, including downregulation of HOXA-cluster genes in MLL-rearranged leukemias.8–10 Based on these pre-clinical findings, EPZ-5676 is currently under investigation in a clinical phase I trial (clinicaltrials.gov identifier: 01684150). In the current study, we assessed whether MLL-PTD-positive leukemias that share critical biological features with MLL-rearranged leukemias, such as high expression of HOXA-cluster genes, similarly require DOT1L.

MLL partial tandem duplication leukemia cells are sensitive to small molecule DOT1L inhibition