Dnmt3a loss and Idh2 neomorphic mutations mutually potentiate malignant hematopoiesis

Abstract

Mutations in the epigenetic regulators DNMT3A and IDH1/2 co-occur in patients with acute myeloid leukemia and lymphoma. In this study, these 2 epigenetic mutations cooperated 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 observed an epigenomic dysregulation with the gain of repressive H3K9 trimethylation and loss of H3K9 acetylation in diseased mouse bone marrow hematopoietic stem and progenitor cells (HSPCs). HDAC inhibitors rapidly reversed the H3K9 methylation/acetylation imbalance in diseased mouse HSPCs while reducing the leukemia burden. In addition, using targeted metabolomic profiling for the first time in mouse leukemia models, we also showed that prostaglandin E2 is overproduced in double-mutant HSPCs, rendering them sensitive to prostaglandin synthesis inhibition. These data revealed 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.

Clinical implications of recurrent gene mutations in acute myeloid leukemia

“…DNMT3A and IDH2 mutations are synergistic events in leukemogenesis. Hematopoietic stem and progenitor cells carrying both mutations are sensitive to induced differentiation by the inhibition of both prostaglandin synthesis and HDAC [97]. However, the mutations in DNMT3A, commonly found in adults, were conspicuously absent from virtually all pediatric cases.…”

Isocitrate Dehydrogenase Mutations in Myelodysplastic Syndromes and in Acute Myeloid Leukemias

“…In spite of the antagonism between IDH and DNMT3A mutations concerning the DNA methylation effects, these two epigenetic mutations were recently shown to cooperate to induce leukemia [ 113 ]. Leukemia-initiating cells isolated from a DNMT3A deficient mouse that expresses an IDH2 mutant displays a megakaryocyte-erythroid progenitor-like phenotype, activates a stem-like gene signature, represses differentiated progenitor genes, and displays an epigenomic dysregulation [ 114 ].…”

Integrin α9β1: a new target to fight thrombosis

“…In this issue of Blood, Dhanesha et al explore the role of myeloid cell-specific integrin a9b1 in arterial thrombosis. 1 They demonstrate that genetic ablation or pharmacologic inhibition of the integrin reduces thrombosis and, importantly, this effect is not accompanied by impairment of normal hemostasis.…”

“…Looking forward, this could make thrombosis treatment safer and more efficient. In this issue of Blood, Al-Sawaf et al 1 show that a complex karyotype (CKT, defined as 3 or more chromosomal abnormalities in 2 or more metaphases) has predictive value in treatment-naive patients with chronic lymphocytic leukemia (CLL) who received chlorambucil-obinutuzumab (ClbG) in the randomized CLL14 trial, 2 whereas in patients randomized to receive venetoclaxobinutuzumab (VenG), the CKT did not impact the clinical outcome.…”

“…Clb, chlorambucil; FCR, fludarabine, cyclophosphamide, rituximab; G, obinutuzumab. 1,[7][8][9][10][11][12][13][14]…”