State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
Department of Hematology, the Second Hospital of Tianjin Medical University, Tianjin, China.
Invest New Drugs. 2022 Dec;40(6):1194-1205. doi: 10.1007/s10637-022-01297-5. Epub 2022 Aug 31.
The V617F mutation in Janus kinase 2 is considered one of the driver mutations leading to Philadelphia-negative myeloproliferative neoplasms (MPNs). Concurrent JAK2 and ASXL1 mutations 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 carrying JAK2 and ASXL1 double mutations. RNA sequencing indicated overactivated oxidative phosphorylation in JAK2;Asxl1 cKit cells. The cell line model with JAK2 and ASXL1 double 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 with JAK2 and ASXL1 double mutations were significantly lower than those of cells with only the JAK2 mutation. 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 concurrent JAK2 and ASXL1 mutations. In conclusion, we provide preclinical evidence showing that the combination of ruxolitinib and ABT-737 is a promising therapeutic strategy for MPN patients with concurrent JAK2 and ASXL1 mutations.
JAK2 中的 V617F 突变被认为是导致费城阴性骨髓增殖性肿瘤（MPN）的驱动突变之一。同时存在 JAK2 和 ASXL1 突变会加速 MPN 患者的纤维化进展。目前针对这两种突变的治疗方法很少。在我们的研究中，评估了 ruxolitinib 与 ABT-737 联合用于携带 JAK2 和 ASXL1 双突变的细胞。RNA 测序表明 JAK2;Asxl1 cKit 细胞中氧化磷酸化过度激活。具有 JAK2 和 ASXL1 双突变的细胞系模型（HEL-AKO 细胞）也表现出线粒体功能失调，活性氧水平增加，ATP 水平降低。具有 JAK2 和 ASXL1 双突变的细胞的集落生长抑制率明显低于仅具有 JAK2 突变的细胞。联合使用 ruxolitinib 和 ABT-737 可促进 HEL-AKO 细胞凋亡并抑制其增殖。两种药物的联合治疗还抑制了同时存在 JAK2 和 ASXL1 突变的患者骨髓单个核细胞的生长。总之，我们提供了临床前证据，表明 ruxolitinib 和 ABT-737 的联合治疗是一种有前途的治疗策略，可用于同时存在 JAK2 和 ASXL1 突变的 MPN 患者。
