{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T22:46:10Z","timestamp":1780958770664,"version":"3.54.1"},"reference-count":45,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2024,7,27]],"date-time":"2024-07-27T00:00:00Z","timestamp":1722038400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Research Council (ERC)","award":["725725"],"award-info":[{"award-number":["725725"]}]},{"name":"AIRC\/FIRC fellowship for Italy","award":["725725"],"award-info":[{"award-number":["725725"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>How hematopoietic stem and progenitor cell (HSPC) fate decisions are affected by genetic alterations acquired during AML leukemogenesis is poorly understood and mainly explored in animal models. Here, we study isocitrate dehydrogenase (IDH) gene mutations in the human model of HSPC and discuss the available literature on this topic. IDH1\/2 mutations occur in ~20% of AML cases, are recognized among the mutations earliest acquired during leukemogenesis, and are targets of specific inhibitors (ivosidenib and enasidenib, respectively). In order to investigate the direct effects of these mutations on HSPCs, we expressed IDH1-R132H or IDH2-R140Q mutants into human CD34+ healthy donor cells via lentiviral transduction and analyzed the colony-forming unit (CFU) ability. CFU ability was dramatically compromised with a complete trilineage block of differentiation. Strikingly, the block was reversed by specific inhibitors, confirming that it was a specific effect induced by the mutants. In line with this observation, the CD34+ leukemic precursors isolated from a patient with IDH2-mutated AML at baseline and during enasidenib treatment showed progressive and marked improvements in their fitness over time, in terms of CFU ability and propensity to differentiate. They attained clonal trilinear reconstitution of hematopoiesis and complete hematological remission.<\/jats:p>","DOI":"10.3390\/cancers16152675","type":"journal-article","created":{"date-parts":[[2024,7,29]],"date-time":"2024-07-29T09:50:05Z","timestamp":1722246605000},"page":"2675","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The Leukemic Isocitrate Dehydrogenase (IDH) 1\/2 Mutations Impair Myeloid and Erythroid Cell Differentiation of Primary Human Hematopoietic Stem and Progenitor Cells (HSPCs)"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3010-5378","authenticated-orcid":false,"given":"Sara","family":"Pierangeli","sequence":"first","affiliation":[{"name":"Hematology and Clinical Immunology Section, Department of Medicine and Surgery, Center for Hemato-Oncological Research (CREO), University of Perugia, 06123 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9419-4544","authenticated-orcid":false,"given":"Serena","family":"Donnini","sequence":"additional","affiliation":[{"name":"Hematology and Clinical Immunology Section, Department of Medicine and Surgery, Center for Hemato-Oncological Research (CREO), University of Perugia, 06123 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerio","family":"Ciaurro","sequence":"additional","affiliation":[{"name":"MD Anderson Cancer Center, University of Texas, TX 78712, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Milano","sequence":"additional","affiliation":[{"name":"Hematology and Clinical Immunology Section, Department of Medicine and Surgery, Center for Hemato-Oncological Research (CREO), University of Perugia, 06123 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Cardinali","sequence":"additional","affiliation":[{"name":"Hematology and Clinical Immunology Section, Department of Medicine and Surgery, Center for Hemato-Oncological Research (CREO), University of Perugia, 06123 Perugia, Italy"},{"name":"Hematology Department, \u2018Santa Maria della Misericordia\u2019 Perugia Hospital, 06129 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofia","family":"Sciabolacci","sequence":"additional","affiliation":[{"name":"Hematology Department, \u2018Santa Maria della Misericordia\u2019 Perugia Hospital, 06129 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4879-7824","authenticated-orcid":false,"given":"Gaetano","family":"Cimino","sequence":"additional","affiliation":[{"name":"Hematology and Clinical Immunology Section, Department of Medicine and Surgery, Center for Hemato-Oncological Research (CREO), University of Perugia, 06123 Perugia, Italy"},{"name":"Hematology Department, \u2018Santa Maria della Misericordia\u2019 Perugia Hospital, 06129 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilaria","family":"Gionfriddo","sequence":"additional","affiliation":[{"name":"Hematology and Clinical Immunology Section, Department of Medicine and Surgery, Center for Hemato-Oncological Research (CREO), University of Perugia, 06123 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Ranieri","sequence":"additional","affiliation":[{"name":"Hematology and Clinical Immunology Section, Department of Medicine and Surgery, Center for Hemato-Oncological Research (CREO), University of Perugia, 06123 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina","family":"Cipriani","sequence":"additional","affiliation":[{"name":"Hematology and Clinical Immunology Section, Department of Medicine and Surgery, Center for Hemato-Oncological Research (CREO), University of Perugia, 06123 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-8675-8581","authenticated-orcid":false,"given":"Eleonora","family":"Padiglioni","sequence":"additional","affiliation":[{"name":"Hematology and Clinical Immunology Section, Department of Medicine and Surgery, Center for Hemato-Oncological Research (CREO), University of Perugia, 06123 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Iacucci Ostini","sequence":"additional","affiliation":[{"name":"Hematology Department, \u2018Santa Maria della Misericordia\u2019 Perugia Hospital, 06129 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiziana","family":"Zei","sequence":"additional","affiliation":[{"name":"Hematology Department, \u2018Santa Maria della Misericordia\u2019 Perugia Hospital, 06129 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Pierini","sequence":"additional","affiliation":[{"name":"Hematology and Clinical Immunology Section, Department of Medicine and Surgery, Center for Hemato-Oncological Research (CREO), University of Perugia, 06123 Perugia, Italy"},{"name":"Hematology Department, \u2018Santa Maria della Misericordia\u2019 Perugia Hospital, 06129 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9139-1729","authenticated-orcid":false,"given":"Maria Paola","family":"Martelli","sequence":"additional","affiliation":[{"name":"Hematology and Clinical Immunology Section, Department of Medicine and Surgery, Center for Hemato-Oncological Research (CREO), University of Perugia, 06123 Perugia, Italy"},{"name":"Hematology Department, \u2018Santa Maria della Misericordia\u2019 Perugia Hospital, 06129 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2059","DOI":"10.1056\/NEJMoa1301689","article-title":"Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia","volume":"368","author":"Ley","year":"2013","journal-title":"N. 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