Current therapy for myelofibrosis (MF) results in a limited prolongation of patient survival. In order to improve treatment outcomes, we developed a strategy to effectively deplete MF hematopoietic stem/progenitor cells (HSPCs). In the present study, an imipridone, ONC201, was combined with RG7112, an antagonist of MDM2, a p53 negative regulator, to activate downstream events of the p53 and TNF-related apoptosis-inducing ligand (TRAIL)/death receptor (DR) pathways. As compared to treatment with the individual drugs, the combination of ONC201 and RG7112 promoted greater degrees of apoptosis of MF CD34⁺ cells through activation of both p53-dependent and -independent pathways. Importantly, treatment with ONC201-RG7112 not only decreased the number of JAK2V617F⁺ and calreticulin mutated colonies assayed from MF CD34⁺ cells, but allowed for the persistence or appearance of JAK2 wild type colonies. Treatment with ONC201 combined with RG7112 could be a potentially effective strategy for treating MF patients.

目前对骨髓纤维化 (MF) 的治疗只能有限地延长患者的生存期。为了改善治疗结果，我们制定了有效耗尽 MF 造血干/祖细胞 (HSPC) 的策略。在本研究中，亚米利酮 ONC201 与 MDM2 的拮抗剂 RG7112（一种 p53 负调节剂）结合，以激活 p53 和 TNF 相关凋亡诱导配体 (TRAIL)/死亡受体 (DR) 通路的下游事件. 与用单独药物治疗相比，ONC201 和 RG7112 的组合通过激活 p53 依赖性和非依赖性途径促进更大程度的 MF CD34 ^{+细胞凋亡。}重要的是，用 ONC201-RG7112 治疗不仅减少了JAK2V617F ⁺从 MF CD34 ⁺细胞测定的钙网蛋白突变集落，但允许 JAK2 野生型集落的持续存在或出现。用 ONC201 联合 RG7112 治疗可能是治疗 MF 患者的潜在有效策略。