{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T13:12:12Z","timestamp":1790514732021,"version":"4.1.0"},"reference-count":49,"publisher":"American Society of Hematology","issue":"7","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2021,2,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Isocitrate dehydrogenase (IDH) mutations are common genetic alterations in myeloid disorders, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Epigenetic changes, including abnormal histone and DNA methylation, have been implicated in the pathogenic build-up of hematopoietic progenitors, but it is still unclear whether and how IDH mutations themselves affect hematopoiesis. Here, we show that IDH1-mutant mice develop myeloid dysplasia in that these animals exhibit anemia, ineffective erythropoiesis, and increased immature progenitors and erythroblasts. In erythroid cells of these mice, D-2-hydroxyglutarate, an aberrant metabolite produced by the mutant IDH1 enzyme, inhibits oxoglutarate dehydrogenase activity and diminishes succinyl\u2013coenzyme A (CoA) production. This succinyl-CoA deficiency attenuates heme biosynthesis in IDH1-mutant hematopoietic cells, thus blocking erythroid differentiation at the late erythroblast stage and the erythroid commitment of hematopoietic stem cells, while the exogenous succinyl-CoA or 5-ALA rescues erythropoiesis in IDH1-mutant erythroid cells. Heme deficiency also impairs heme oxygenase-1 expression, which reduces levels of important heme catabolites such as biliverdin and bilirubin. These deficits result in accumulation of excessive reactive oxygen species that induce the cell death of IDH1-mutant erythroid cells. Our results clearly show the essential role of IDH1 in normal erythropoiesis and describe how its mutation leads to myeloid disorders. These data thus have important implications for the devising of new treatments for IDH-mutant tumors.<\/jats:p>","DOI":"10.1182\/blood.2020007075","type":"journal-article","created":{"date-parts":[[2020,11,30]],"date-time":"2020-11-30T21:50:41Z","timestamp":1606773041000},"page":"945-958","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":40,"title":["<i>IDH1<\/i> mutation contributes to myeloid dysplasia in mice by disturbing heme biosynthesis and erythropoiesis"],"prefix":"10.1182","volume":"137","author":[{"given":"Yu","family":"Gu","sequence":"first","affiliation":[{"name":"State Key Laboratory of Cancer Biology\u2013Department of Pathology, Xijing Hospital;"},{"name":"Department of Pathology, Basic Medicine School, Fourth Military Medical University, Xi\u2019an, Shaanxi, China;"},{"name":"The Princess Margaret Cancer Centre\u2013Ontario Cancer Institute, University Health Network, Toronto, ON, 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