The Leukemic Isocitrate Dehydrogenase (IDH) 1/2 Mutations Impair Myeloid and Erythroid Cell Differentiation of Primary Human Hematopoietic Stem and Progenitor Cells (HSPCs)
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Le résumé fourni par la source
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.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- The Leukemic Isocitrate Dehydrogenase (IDH) 1/2 Mutations Impair Myeloid and Erythroid Cell Differentiation of Primary Human Hematopoietic Stem and Progenitor Cells (HSPCs)
- Date Crossref
- 27/07/2024
- Éditeur
- MDPI AG
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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University of Perugia Hematology and Clinical Immunology Section pays non établi dans la noticeUniversité ou école supérieure
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The University of Texas MD Anderson Cancer Center MD Anderson Cancer Center pays non établi dans la noticeÉtablissement de santé
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Azienda Ospedaliera di Perugia pays non établi dans la noticeÉtablissement de santé
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Ospedale Santa Maria pays non établi dans la noticeÉtablissement de santé
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‘Santa Maria della Misericordia’ Perugia Hospital Hematology Department pays non établi dans la noticeÉtablissement de santé
Hematology and Clinical Immunology Section — University of Perugia, MD Anderson Cancer Center — The University of Texas MD Anderson Cancer Center et Azienda Ospedaliera di Perugia, avec 2 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.