Key Points

  • Dnmt3a loss and IDH2 neomorphic mutation synergistically induce hematopoietic malignancy.

  • Dnmt3aKO-IDH2 mutant mouse leukemia is sensitive to HDAC inhibition and overproduces Prostaglandin E2 to maintain abnormal self-renewal.

Mutations in the epigenetic regulators DNMT3A and IDH1/2 co-occur in patients with acute myeloid leukemia and lymphoma. Here, we demonstrate that these two epigenetic mutations cooperate to induce leukemia. Leukemia-initiating cells from Dnmt3a-/- mice that express an IDH2 neomorphic mutant have a megakaryocyte-erythroid progenitor-like immunophenotype, activate a stem-cell-like gene signature, and repress differentiated-progenitor genes. We observe there is an epigenomic dysregulation with the gain of repressive H3K9 trimethylation and loss of H3K9 acetylation in diseased mouse bone marrow stem and progenitor cells (HSPC). Here we found that HDAC inhibitors rapidly reverse the H3K9 methylation/acetylation imbalance in diseased mouse HSPC while reducing the leukemia burden. Additionally, using targeted metabolomic profiling for the first time in mouse leukemia models, we also show that prostaglandin E2 is overproduced in double-mutant hematopoietic stem and progenitor cells (HSPCs), rendering them sensitive to prostaglandin synthesis inhibition. These data reveal that Dnmt3a and Idh2 mutations are synergistic events in leukemogenesis and that HSPCs carrying both mutations are sensitive to induced differentiation by the inhibition of both prostaglandin synthesis and HDAC, which may reveal new therapeutic opportunities for patients carrying IDH1/2 mutations.

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