2. Academic Validation
  3. Combination of ruxolitinib with ABT-737 exhibits synergistic effects in cells carrying concurrent JAK2V617F and ASXL1 mutations

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

  • Invest New Drugs. 2022 Aug 31. doi: 10.1007/s10637-022-01297-5.
Jiajia Yuan 1,  Junzhe Song 1,  Chao Chen 1,  Xue Lv 1,  Jie Bai 2,  Jing Yang 3 4,  Yuan Zhou 5
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Hematology, the Second Hospital of Tianjin Medical University, Tianjin, China.
  • 3 Department of Pathology and Pathophysiology, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou, 311121, China. yjphy@126.com.
  • 4 International Cooperation Laboratory of Stem Cell Research, Hebei Medical University, Shijiazhuang, 050000, China. yjphy@126.com.
  • 5 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. yuanzhou@ihcams.ac.cn.
PMID: 36044173 DOI: 10.1007/s10637-022-01297-5
Abstract

The V617F mutation in Janus kinase 2 is considered one of the driver mutations leading to Philadelphia-negative myeloproliferative neoplasms (MPNs). Concurrent JAK2V617F 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 JAK2V617F and ASXL1 double mutations. RNA Sequencing indicated overactivated Oxidative Phosphorylation in JAK2V617F;Asxl1+/- cKit+ cells. The cell line model with JAK2V617F 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 JAK2V617F and ASXL1 double mutations were significantly lower than those of cells with only the JAK2V617F 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 JAK2V617F 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 JAK2V617F and ASXL1 mutations.

Keywords

Apoptosis; BCL2 inhibitor; MPN; Ruxolitinib.

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