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 studyisocitrate dehydrogenase(IDH) gene mutations in the human model of HSPC and discuss the available literature on this topic.IDH1/2mutations 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 expressedIDH1-R132H orIDH2-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 withIDH2-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.
造血干细胞与祖细胞（HSPC）在急性髓系白血病（AML）发生过程中获得的基因突变如何影响其命运决定，目前尚不明确，且相关研究主要在动物模型中进行。本研究以人类HSPC模型为对象，探讨异柠檬酸脱氢酶（IDH）基因突变，并对该领域的现有文献进行综述。IDH1/2突变约占AML病例的20%，被认为是白血病发生过程中最早获得的突变之一，并且已成为特异性抑制剂（分别为伊沃西尼和恩西地平）的靶点。为探究这些突变对HSPC的直接作用，我们通过慢病毒转导将IDH1-R132H或IDH2-R140Q突变体导入健康供体来源的人CD34+细胞，并分析其集落形成单位（CFU）能力。结果显示CFU能力显著受损，并出现完全的三系分化阻滞。值得注意的是，这种阻滞可被特异性抑制剂逆转，证实其由突变体特异性诱导。与此观察结果一致，从一名IDH2突变AML患者基线期及恩西地平治疗期间分离的CD34+白血病前体细胞，在CFU能力和分化倾向方面均随时间呈现渐进性显著改善。这些细胞实现了克隆性三系造血重建，并达到完全血液学缓解。
肿瘤(癌症)患者之家