Pierangeli Sara, Donnini Serena, Ciaurro Valerio, Milano Francesca, Cardinali Valeria, Sciabolacci Sofia, Cimino Gaetano, Gionfriddo Ilaria, Ranieri Roberta, Cipriani Sabrina, Padiglioni Eleonora, Iacucci Ostini Roberta, Zei Tiziana, Pierini Antonio, Martelli Maria Paola
Hematology and Clinical Immunology Section, Department of Medicine and Surgery, Center for Hemato-Oncological Research (CREO), University of Perugia, 06123 Perugia, Italy.
MD Anderson Cancer Center, University of Texas, TX 78712, USA.
Cancers (Basel). 2024 Jul 27;16(15):2675. doi: 10.3390/cancers16152675.
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 () gene mutations in the human model of HSPC and discuss the available literature on this topic. 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 -R132H or -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 -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.
造血干细胞和祖细胞（HSPC）的命运决定如何受到急性髓系白血病（AML）白血病发生过程中获得的基因改变的影响，目前了解甚少，且主要是在动物模型中进行探索。在此，我们研究HSPC人类模型中的（）基因突变，并讨论关于该主题的现有文献。这些突变发生在约20%的AML病例中，在白血病发生过程中最早获得的突变中被识别出来，并且分别是特定抑制剂（艾伏尼布和恩杂鲁胺）的作用靶点。为了研究这些突变对HSPC的直接影响，我们通过慢病毒转导将-R132H或-R140Q突变体导入人类CD34+健康供体细胞，并分析集落形成单位（CFU）能力。CFU能力显著受损，分化出现完全三系阻滞。引人注目的是，这种阻滞被特定抑制剂逆转，证实这是由突变体诱导的特定效应。与这一观察结果一致，从一名基线时和接受恩杂鲁胺治疗期间患有-突变AML的患者中分离出的CD34+白血病前体细胞，在CFU能力和分化倾向方面，随着时间的推移显示出适应性的逐步显著改善。它们实现了造血的克隆三系重建和完全血液学缓解。
