DOT1L as a therapeutic target for the treatment of DNMT3A-mutant acute myeloid leukemia

Abstract

• Data from Dnmt3a2/2 mice implicate Dot1l as a critical mediator of the malignant gene expression program of Dnmt3a-mediated leukemia.• Pharmacologic inhibition of DOT1L exerts potent antileukemic activity in DNMT3A-mutant human acute myeloid leukemia in vitro and in vivo.Mutations in DNA methyltransferase 3A (DNMT3A) are common in acute myeloid leukemia and portend a poor prognosis; thus, new therapeutic strategies are needed. The likely mechanism by which DNMT3A loss contributes to leukemogenesis is altered DNA methylation and the attendant gene expression changes; however, our current understanding is incomplete. We observed that murine hematopoietic stem cells (HSCs) in which Dnmt3a had been conditionally deleted markedly overexpress the histone 3 lysine 79 (H3K79) methyltransferase, Dot1l. We demonstrate that Dnmt3a 2/2 HSCs have increased H3K79 methylation relative to wild-type (WT) HSCs, with the greatest increases noted at DNA methylation canyons, which are regions highly enriched for genes dysregulated in leukemia and prone to DNA methylation loss with Dnmt3a deletion. These findings led us to explore DOT1L as a therapeutic target for the treatment of DNMT3A-mutant AML. We show that pharmacologic inhibition of DOT1L resulted in decreased expression of oncogenic canyon-associated genes and led to dose-and time-dependent inhibition of proliferation, induction of apoptosis, cell-cycle arrest, and terminal differentiation in DNMT3A-mutant cell lines in vitro. We show in vivo efficacy of the DOT1L inhibitor EPZ5676 in a nude rat xenograft model of DNMT3A-mutant AML. DOT1L inhibition was also effective against primary patient DNMT3A-mutant AML samples, reducing colony-forming capacity (CFC) and inducing terminal differentiation in vitro. These studies suggest that DOT1L may play a critical role in DNMT3A-mutant leukemia. With pharmacologic inhibitors of DOT1L already in clinical trials, DOT1L could be an immediately actionable therapeutic target for the treatment of this poor prognosis disease. (Blood. 2016;128(7):971-981)

Clinical implications ofDNMT3Amutations in a Southeast Asian cohort of acute myeloid leukaemia patients

“…At the same time, epigenetic changes such as altered histone methylation are often reversible and are therefore excellent pharmacological targets 37. Therefore, novel epigenetic therapies are currently being developed and studied in clinical trials, holding great promise in the treatment of AML38 In particular, DNMT3A has been identified as a potential therapeutic biomarker, with the identification of DOT1L as a therapeutic target for DNMT3A -mutated AML 39…”

Isocitrate Dehydrogenase Mutations in Human Cancers: Physiopathologic Mechanisms and Therapeutic Targeting

“…In this context, particularly interesting and reminiscent of the observations made for IDH-mutant leukemic cells, are the results reported in a recent study showing that loss-of-function DNMT3A mutations can determine overexpression of the lysine methyltransferase DOT1L. 108 Pharmacological inhibition of the DOT1L inhibitor EPZ5676 displayed antitumor activity in vivo, as evidenced in a nude rat xenograft model of DNMT3A-mutant AML. Specifically, the DOT1L inhibition elicited an antileukemic effect against primary DNMT3A-mutant AML cells, reducing their clonogenetic capacity and inducing their differentiation.…”

“…Specifically, the DOT1L inhibition elicited an antileukemic effect against primary DNMT3A-mutant AML cells, reducing their clonogenetic capacity and inducing their differentiation. 108 Tateishi and colleagues have identified an alternative strategy to metabolically target IDH-mutant tumor cells. 109 The initial analysis involved the effects of deregulated Myc that had been observed in many tumors, regarding the metabolic state; the features examined included increased glycolytic rate and glutaminolysis to meet the increased biosynthetic demand of cancer cells.…”

Biology of DNMT3 and LSD1 inhibition in acute myeloid leukaemia (AML)

“…Moreover, the speculation that the LSD1 inhibition suppress DNMT3A activity is supported by fluorescence polarization and isothermal titration calorimetry experiments [52,65] Work by Petell and coworkers shows that LSD1-facilitated interaction of Dnmt3a with histone tails, which is reduced by LSD1 inhibitor treatment [11]. An innovative approach could interfere effectively without blocking the target enzymatic activity by using peptide against specific region of the two enzymes to provide novel, specific, low-toxicity treatment agents to supplement current reatment protocols [66][67][68][69][70][71][72][73][74][75][76][77][78][79][80][81][82][83][84]. …”