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

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Summary

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.

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Funding

This work was supported in part by National Key Research and Development Program of China (grant number 2020YFE0203000); National Natural Science Foundation of China (grant numbers 81970120, 81770128, 81900249); Natural Science Foundation of Hebei Province (H2020206003); Key Project of Science and Technology Research Project of Hebei Universities (ZD2021069).

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Authors and 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

    Jiajia Yuan, Junzhe Song, Chao Chen, Xue Lv & Yuan Zhou

  2. Department of Hematology, the Second Hospital of Tianjin Medical University, Tianjin, China

    Jie Bai

  3. Department of Pathology and Pathophysiology, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou, 311121, China

    Jing Yang

  4. International Cooperation Laboratory of Stem Cell Research, Hebei Medical University, Shijiazhuang, 050000, China

    Jing Yang

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JJY and YZ designed the study. JJY and JZS performed the experiments. JJY, CC, JY and YZ discussed and analyzed the data. JJY, XL, JY and YZ drafted the manuscript. JB analyzed the patients’ information. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Jing Yang or Yuan Zhou.

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Ethical approval for this project was obtained from the Ethics Committee of Blood Diseases Hospital, Chinese Academy of Medical Sciences. Four patient samples were collected and processed immediately after bone marrow puncture. Written informed consent was obtained according to the Declaration of Helsinki.

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Yuan, J., Song, J., Chen, C. et al. Combination of ruxolitinib with ABT-737 exhibits synergistic effects in cells carrying concurrent JAK2V617F and ASXL1 mutations. Invest New Drugs 40, 1194–1205 (2022). https://doi.org/10.1007/s10637-022-01297-5

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