Combination of ruxolitinib with ABT-737 exhibits synergistic effects in cells carrying concurrent JAK2V617F and ASXL1 mutations

The V617F mutation in Janus kinase 2 is considered one of the driver mutations leading to Philadelphia-negative myeloproliferative neoplasms (MPNs). Concurrent JAK2^V617F 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^V617F and ASXL1 double mutations. RNA sequencing indicated overactivated oxidative phosphorylation in JAK2^V617F;Asxl1^+/- cKit⁺ cells. The cell line model with JAK2^V617F 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^V617F and ASXL1 double mutations were significantly lower than those of cells with only the JAK2^V617F 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^V617F 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^V617F and ASXL1 mutations.