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Cotargeting the JAK/STAT signaling pathway and histone deacetylase by ruxolitinib and vorinostat elicits synergistic effects against myeloproliferative neoplasms

Summary

The majority of patients with Philadelphia-negative myeloproliferative neoplasms (MPNs) harbor a gain of function mutation V617F in Janus kinase (JAK) 2. Although JAK2 inhibitors such as ruxolitinib have been shown to be clinically efficacious, the hematological toxicity and eventual drug resistance limit its use as monotherapy. Other gene mutations or dysregulation correlated with the disease phenotype and prognosis have been found to contribute to the complexity and heterogeneity of MPNs, giving rise to an increasing demand for combination therapies. Here, we combine ruxolitinib and the histone deacetylase inhibitor vorinostat as a rational combination strategy for MPNs. We tested the combination of ruxolitinib and vorinostat in cells with the JAK2V617F mutation, such as HEL cells, c-Kit+ cells from JAK2V617F transgenic mice and bone marrow mononuclear cells (BMMNCs) from patients with MPN. Our results showed significant synergistic effects of this combination strategy. Cotreatment with ruxolitinib and vorinostat synergistically induced apoptosis, cell cycle arrest and inhibition of the colony-forming capacity of HEL cells by attenuating the JAK/signal transducer and activator of transcription (STAT) and protein kinase-B (AKT) signaling pathways. In particular, cotreatment with ruxolitinib and vorinostat prevented the formation of large colonies of colony-forming unit-granulocyte/erythroid/macrophage/megakaryocytes (CFU-GEMMs) and colony-forming unit-granulocyte/macrophages (CFU-GMs) derived from the BMMNCs of patients with MPN. Taken together, these data provided preclinical evidence that the combination of ruxolitinib and vorinostat is a potential dual-target therapy for patients with MPN.

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Funding

This work was supported by grants from the National Natural Science Foundation of China (81770128), Chinese Academy of Medical Sciences (2016-I2M-2-001, 1002-1-22), and Tianjin Municipal Science and Technology Commission (16JCZDJC34500).

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Correspondence to Jie Bai 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. Thirteen 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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Hao, X., Xing, W., Yuan, J. et al. Cotargeting the JAK/STAT signaling pathway and histone deacetylase by ruxolitinib and vorinostat elicits synergistic effects against myeloproliferative neoplasms. Invest New Drugs 38, 610–620 (2020). https://doi.org/10.1007/s10637-019-00794-4

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Keywords

  • Myeloproliferative neoplasms
  • JAK2V617F
  • HDAC
  • Ruxolitinib
  • Vorinostat
  • Combination therapy