TY - JOUR
T1 - DOT1L as a therapeutic target for the treatment of DNMT3A-mutant acute myeloid leukemia
AU - Rau, Rachel E.
AU - Rodriguez, Benjamin A.
AU - Luo, Min
AU - Jeong, Mira
AU - Rosen, Allison
AU - Rogers, Jason H.
AU - Campbell, Carly T.
AU - Daigle, Scott R.
AU - Deng, Lishing
AU - Song, Yongcheng
AU - Sweet, Steve
AU - Chevassut, Timothy
AU - Andreeff, Michael
AU - Kornblau, Steven M.
AU - Li, Wei
AU - Goodell, Margaret A.
N1 - Funding Information:
The authors thank members of the Goodell Laboratory for helpful discussions; Y. Zheng, A. Guzman, and R. Gupta for technical support; C. Gillespie for critical review of the manuscript; M. Redell and M. Minden for providing cell lines; and J. Matthews and S. Piece for assistance with patient samples. This work was supported by The Faust Foundation (R.E.R.); Edward P. Evans Foundation, Samuel Waxman Cancer Research Foundation, Henry Malvin Helis Foundation, and Lester and Sue Smith Foundation (M.A.G.); and the National Institutes of Health (NIH), National Cancer Institute (grants CA090433-11 [R.E.R.] and CA183252, CA183252, and CA126752), National Institute of Diabetes and Digestive and Kidney Diseases (grants DK092883 and DK084259), National Human Genome Research Institute (grants R01HG007538 and HG007538); and the Cytometry and Cell Sorting Core at Baylor College of Medicine with funding from the NIH, National Institute of Allergy and Infectious Diseases (grant nos. P30 AI036211 and P30 CA125123), National Institute of General Medical Sciences (S10 RR024574), and the expert assistance of J. Sederstrom and A. White.
Publisher Copyright:
© 2016 by The American Society of Hematology.
PY - 2016
Y1 - 2016
N2 - 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-/- 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.
AB - 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-/- 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.
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U2 - 10.1182/blood-2015-11-684225
DO - 10.1182/blood-2015-11-684225
M3 - Article
C2 - 27335278
AN - SCOPUS:84993940217
SN - 0006-4971
VL - 128
SP - 971
EP - 981
JO - Blood
JF - Blood
IS - 7
ER -