Sca1⁺ bone marrow (BM) cells from 3aKO mice were retrovirally transduced with R140Q mutated Idh2 (140) and subsequently transplanted in recipient mice in comparison with their single- and nonmutated WT counterpart cells. Recipients of double-mutated (3aKO-140) cells develop severe hematologic malignancies, including AML, earlier than mice receiving 3aKO cells alone. Lin⁻Kit⁺ cells harvested from 3aKO-140 injected mice induce CMML or AML in all secondary recipients. Multi-omics approaches reveal an imbalance of H3K9 methylation vs acetylation and overproduction of AA and PGE2. Treatment of mice with the HDACi restores normal levels of H3K9 methylation and acetylation and improves survival of 3aKO-140 injected mice. Ex vivo treatment with celecoxib of 3aKO-140, but not single- or nonmutated progenitors, reduces colony-forming units (CFU) and leukemic engraftment upon retransplantation. incl., including.