DOT1L submitted manuscript.pdf (2.7 MB)
DOT1L as a therapeutic target for the treatment of DNMT3A-mutant acute myeloid leukemia
journal contribution
posted on 2023-06-09, 04:15 authored by Rachel E Rau, Benjamin A Rodriguez, Min Luo, Mira Jeong, Allison Rosen, Jason H Rogers, Carly T Campbel, Scott R Daigle, Lishing Deng, Yongcheng Song, Steve Sweet, Timothy ChevassutTimothy Chevassut, Michael Andreeff, Steven M Kornblau, Wei Li, Margaret A GoodellMutations 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(-/-) 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.
History
Publication status
- Published
File Version
- Accepted version
Journal
BloodISSN
0006-4971Publisher
American Society of HematologyExternal DOI
Issue
7Volume
128Page range
971-981Department affiliated with
- Clinical and Experimental Medicine Publications
Research groups affiliated with
- Haematology Research Group Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2016-11-29First Open Access (FOA) Date
2017-06-22First Compliant Deposit (FCD) Date
2016-11-28Usage metrics
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