Combination of ruxolitinib with ABT-737 exhibits synergistic effects in cells carrying concurrent JAK2V617Fand ASXL1 mutations
Combination of ruxolitinib with ABT-737 exhibits synergistic effects in cells carrying concurrent JAK2V617Fand ASXL1 mutations
复制标题
鲁索替尼与 ABT-737 的组合在同时携带 JAK2V617F 和 ASXL1 突变的细胞中表现出协同作用
DOI：
10.1007/s10637-022-01297-5
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发表时间：
2022
影响因子：
3.4
通讯作者：
Yuan Zhou
中科院分区：
文献类型：
--
作者：
Jiajia Yuan;Junzhe Song;Chao Chen;Xue Lv;Jie Bai;Jing Yang;Yuan Zhou
Janus激酶2中的V617 F突变被认为是导致费城阴性骨髓增生性肿瘤（MPN）的驱动突变之一。JAK 2 V617 F1和ASXL 1同时突变加速了MPN患者骨髓纤维化的进展目前很少有治疗方法可用于这两种突变的患者。在我们的研究中，ruxolitinib与ABT-737的组合在携带JAK 2 V617 FandASXL 1双突变的细胞中进行了评估。RNA测序显示JAK 2 V617 F; Asxl 1 +/-cKit+细胞中氧化磷酸化过度激活。具有JAK 2 V617 F和ASXL 1双突变的细胞系模型（HEL-AKO细胞）也表现出线粒体功能失调，活性氧水平升高，ATP水平降低。JAK 2 V617 F和ASXL 1双突变细胞的殖民地生长抑制率显著低于仅JAK 2 V617 F突变细胞。Ruxolitinib联合ABT-737可促进HEL-AKO细胞凋亡，抑制其增殖。两种药物的联合治疗也抑制了从同时携带JAK 2 V617 F和ASXL 1突变的患者中分离的骨髓单个核细胞的生长。总之，我们提供的临床前证据表明，ruxolitinib和ABT-737的组合是一个有前途的治疗策略，同时JAK 2 V617 FandASXL 1突变的MPN患者。
The V617F mutation in Janus kinase 2 is considered one of the driver mutations leading to Philadelphia-negative myeloproliferative neoplasms (MPNs). ConcurrentJAK2V617FandASXL1mutations accelerate the progression of myelofibrosis in patients with MPNs. Few therapies are currently available for patients with these two mutations. In our study, the combination of ruxolitinib with ABT-737 was evaluated in cells carryingJAK2V617FandASXL1double mutations. RNA sequencing indicated overactivated oxidative phosphorylation inJAK2V617F;Asxl1+/-cKit+cells. The cell line model withJAK2V617FandASXL1double mutations (HEL-AKO cells) also exhibited dysregulated mitochondrial function with an increase in the reactive oxygen species levels and a decrease in the ATP levels. The colony growth inhibition rates of cells withJAK2V617FandASXL1double mutations were significantly lower than those of cells with only theJAK2V617Fmutation. Combined treatment with ruxolitinib and ABT-737 promoted apoptosis and inhibited the proliferation of HEL-AKO cells. Cotreatment with the two drugs also inhibited the growth of bone marrow mononuclear cells isolated from patients with concurrentJAK2V617FandASXL1mutations. In conclusion, we provide preclinical evidence showing that the combination of ruxolitinib and ABT-737 is a promising therapeutic strategy for MPN patients with concurrentJAK2V617FandASXL1mutations.