1. Dnmt3a loss and Idh2 neomorphic mutations mutually potentiate malignant hematopoiesis
- Author
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Margaret A. Goodell, Xue Qing David Wang, Carina Rosas, Anna Guzman, Xiaotian Zhang, Mira Jeong, Ting Zhou, Yun Huang, Wei Li, Nagireddy Putluri, Ying Qu, Jianzhong Su, Arun Sreekumar, and Xinyu Wang
- Subjects
0301 basic medicine ,Immunology ,Biology ,Biochemistry ,Cell Line ,DNA Methyltransferase 3A ,Histones ,03 medical and health sciences ,Mice ,0302 clinical medicine ,medicine ,Animals ,Humans ,Metabolomics ,Genetic Predisposition to Disease ,Epigenetics ,DNA (Cytosine-5-)-Methyltransferases ,Progenitor cell ,Genetic Association Studies ,Epigenomics ,Mice, Knockout ,Myeloid Neoplasia ,Gene Expression Profiling ,Myeloid leukemia ,Cell Biology ,Hematology ,DNA Methylation ,medicine.disease ,Isocitrate Dehydrogenase ,Hematopoiesis ,Haematopoiesis ,Leukemia ,Disease Models, Animal ,030104 developmental biology ,Cell Transformation, Neoplastic ,030220 oncology & carcinogenesis ,Hematologic Neoplasms ,Mutation ,Cancer research ,Metabolome ,Chromatin Immunoprecipitation Sequencing ,Histone deacetylase ,Stem cell - 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.
- Published
- 2019