Mutant DNMT3A promotes leukemogenesis via aberrant epigenetic induction of stem-cell genes.

  • Major finding: Mutant DNMT3A promotes leukemogenesis via aberrant epigenetic induction of stem-cell genes.

  • Concept: DOT1L inhibition reverses mutant DNMT3A–induced gene expression patterns, suppressing leukemogenesis.

  • Impact: DOT1L targeting may provide therapeutic benefit in patients with DNMT3A-mutated leukemia.

Mutations in DNA methyltransferase 3A (DNMT3A), most commonly DNMT3AR882H, occur frequently in acute myeloid leukemia (AML), often together with other mutations. To gain insight into the mechanism by which mutant DNMT3A promotes leukemia and whether mutant DNMT3A cooperates with secondary mutations to induce leukemogenesis, Lu and colleagues transplanted mice with hematopoietic stem/progenitor cells (HSPC) expressing wild-type DNMT3A or DNMT3AR882H with NRASG12D. DNMT3AR882H accelerated leukemogenesis in the presence of NRASG12D, whereas DNMT3AR882H did not induce disease and wild-type DNMT3A suppressed leukemogenesis. Additionally, DNMT3AR882H enhanced the ability of progenitor cells to be serially transplanted in vivo, indicative of increased leukemia-initiating stem cell (LSC) characteristics, and increased expression of stemness genes. Chromatin immunoprecipitation sequencing indicated that DNMT3AR882H binding was enhanced at enhancers and at CpG dinucleotides. DNMT3AR882H led to hypomethylation of CpGs at cis-regulatory sites of essential stemness genes, and increased H3K27 acetylation, an activating histone mark, at gene-regulatory elements, altogether providing a mechanism by which DNMT3AR882H may activate enhancers and promote expression of AML-associated genes. Similar hypomethylation patterns were observed in human patients with DNMT3AR882H AML. To potentially reverse the defects of DNMT3AR882H, inhibitors of epigenetic regulators were screened, and DNMT3AR882H;NRASG12D LSCs exhibited enhanced sensitivity to an inhibitor of the H3K79 methyltransferase DOT1L. DOT1L inhibition reduced expression of DNMT3AR882H-induced stemness genes, suppressed the growth of DNMT3AR882H AML cells, and delayed AML progression in vivo. Consistent with these findings, Rau and colleagues also identified DOT1L as a critical mediator of DNMT3A-mutant AML. Dnmt3a

Lu R, Wang P, Parton T, Zhou Y, Chrysovergis K, Rockowitz S, et al. Epigenetic perturbations by Arg882-mutated DNMT3A potentiate aberrant stem cell gene-expression program and acute leukemia development. Cancer Cell 2016;30:92–107.

Rau RE, Rodriguez B, Luo M, Jeong M, Rosen A, Rogers JH, et al. DOT1L as a therapeutic target for the treatment of DNMT3A-mutant acute myeloid leukemia. Blood 2016 Jun 22 [Epub ahead of print].

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