Mahfoudhi Emna, Lordier Larissa, Marty Caroline, Pan Jiajia, Roy Anita, Roy Lydia, Rameau Philippe, Abbes Salem, Debili Najet, Raslova Hana, Chang Yunhua, Debussche Laurent, Vainchenker William, Plo Isabelle
INSERM, UMR 1170, Laboratory of Excellence GR-Ex, Villejuif, France.
UMR 1170, Université Paris-Saclay, Gustave Roussy, Villejuif, France.
Oncotarget. 2016 May 31;7(22):31980-92. doi: 10.18632/oncotarget.7881.
TP53 also known as p53 is a tumor suppressor gene mutated in a variety of cancers. P53 is involved in cell cycle, apoptosis and DNA repair mechanisms and is thus tightly controlled by many regulators. Recently, strategies to treat cancer have focused on the development of MDM2 antagonists to induce p53 stabilization and restore cell death in p53 non-mutated cancers. However, some of these molecules display adverse effects in patients including induction of thrombocytopenia. In the present study, we have explored the effect of SAR405838 not only on human megakaryopoiesis but also more generally on hematopoiesis. We compared its effect to MI-219 and Nutlin, which are less potent MDM2 antagonists than SAR405838. We found that all these compounds induce a deleterious effect on all types of hematopoietic progenitors, as well as on erythroid and megakaryocytic differentiation. Moreover, they inhibit both early and late stages of megakaryopoiesis including ploidization and proplatelet formation. In conclusion, MDM2 antagonists induced a major hematopoietic defect in vitro as well as an inhibition of all stages of megakaryopoiesis that may account for in vivo thrombocytopenia observed in treated patients.
TP53也被称为p53，是一种在多种癌症中发生突变的肿瘤抑制基因。p53参与细胞周期、细胞凋亡和DNA修复机制，因此受到许多调节因子的严格控制。最近，治疗癌症的策略集中在开发MDM2拮抗剂，以诱导p53稳定并恢复p53未突变癌症中的细胞死亡。然而，其中一些分子在患者中显示出不良反应，包括诱导血小板减少症。在本研究中，我们不仅探讨了SAR405838对人类巨核细胞生成的影响，还更广泛地探讨了其对造血作用的影响。我们将其作用与MI-219和Nutlin进行了比较，这两种MDM2拮抗剂的效力均低于SAR405838。我们发现，所有这些化合物对所有类型的造血祖细胞以及红系和巨核系分化均产生有害作用。此外，它们抑制巨核细胞生成的早期和晚期阶段，包括多倍体化和前血小板形成。总之，MDM2拮抗剂在体外诱导了严重的造血缺陷以及对巨核细胞生成所有阶段的抑制，这可能解释了在接受治疗的患者中观察到的体内血小板减少症。
