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A drug targeting 5‑lipoxygenase enhances the activity of a JAK2 inhibitor in CD34+ bone marrow cells from patients with JAK2V617F‑positive polycythemia vera in vitro

  • Authors:
    • Yuan Chen
    • Hu Zhao
    • Jing Luo
    • Youping Liao
    • Kui Tan
    • Guoyu Hu
  • View Affiliations / Copyright

    Affiliations: Department of Hematology, The Affiliated Zhuzhou Hospital Xiangya Medical College CSU, Zhuzhou, Hunan 412000, P.R. China
    Copyright: © Chen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 351
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    Published online on: March 4, 2021
       https://doi.org/10.3892/ol.2021.12612
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Abstract

Janus kinase 2 (JAK2) inhibitors, the first targeted treatments for myeloproliferative neoplasms (MPNs), provide substantial benefits, including a marked reduction in splenomegaly and MPN‑associated symptoms. However, these drugs rarely induce molecular remission in patients with MPNs. Zileuton, a 5‑lipoxygenase (5‑LO) inhibitor, has been demonstrated to selectively deplete hematopoietic stem cells (HSCs) expressing a JAK2 point mutation (JAK2V617F) in mouse models of JAK2V617F‑induced polycythemia vera (PV). To determine the potential activity of 5‑LO inhibitors in combination with JAK inhibitors against human PV HSCs, the present study first analyzed 5‑LO expression in CD34+ bone marrow cells from patients with JAK2V617F‑positive PV using western blotting and reverse transcription‑quantitative PCR, and then examined the effect of zileuton combined with ruxolitinib on colony formation using a colony formation assay. Furthermore, cell cycle and apoptosis in CD34+ cells from patients with PV and healthy volunteers were determined by flow cytometry. In the present study, 5‑LO expression was upregulated in CD34+ cells from patients with PV compared with in CD34+ cells from healthy volunteers. Higher levels of leukotriene B4, a product of the 5‑LO signaling pathway, were detected in patients with PV compared with in healthy volunteers. Zileuton treatment suppressed the colony formation of CD34+ cells from patients with PV in a dose‑dependent manner. Furthermore, zileuton and ruxolitinib exerted their anticancer effects by suppressing hematopoietic colony formation, inducing apoptosis and arresting the cell cycle of human CD34+ cells from patients with PV. The combination of these two drugs exerted a more beneficial effect than either agent alone. Based on these data, zileuton enhanced the antitumor activity of low‑dose ruxolitinib in hematopoietic progenitor cells from patients with PV, providing conceptual validation for further clinical applications of combination treatment with ruxolitinib and zileuton for patients with PV.
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Copy and paste a formatted citation
Spandidos Publications style
Chen Y, Zhao H, Luo J, Liao Y, Tan K and Hu G: A drug targeting 5‑lipoxygenase enhances the activity of a JAK2 inhibitor in CD34<sup>+</sup> bone marrow cells from patients with JAK2V617F‑positive polycythemia vera <em>in vitro</em>. Oncol Lett 21: 351, 2021.
APA
Chen, Y., Zhao, H., Luo, J., Liao, Y., Tan, K., & Hu, G. (2021). A drug targeting 5‑lipoxygenase enhances the activity of a JAK2 inhibitor in CD34<sup>+</sup> bone marrow cells from patients with JAK2V617F‑positive polycythemia vera <em>in vitro</em>. Oncology Letters, 21, 351. https://doi.org/10.3892/ol.2021.12612
MLA
Chen, Y., Zhao, H., Luo, J., Liao, Y., Tan, K., Hu, G."A drug targeting 5‑lipoxygenase enhances the activity of a JAK2 inhibitor in CD34<sup>+</sup> bone marrow cells from patients with JAK2V617F‑positive polycythemia vera <em>in vitro</em>". Oncology Letters 21.5 (2021): 351.
Chicago
Chen, Y., Zhao, H., Luo, J., Liao, Y., Tan, K., Hu, G."A drug targeting 5‑lipoxygenase enhances the activity of a JAK2 inhibitor in CD34<sup>+</sup> bone marrow cells from patients with JAK2V617F‑positive polycythemia vera <em>in vitro</em>". Oncology Letters 21, no. 5 (2021): 351. https://doi.org/10.3892/ol.2021.12612
Copy and paste a formatted citation
x
Spandidos Publications style
Chen Y, Zhao H, Luo J, Liao Y, Tan K and Hu G: A drug targeting 5‑lipoxygenase enhances the activity of a JAK2 inhibitor in CD34<sup>+</sup> bone marrow cells from patients with JAK2V617F‑positive polycythemia vera <em>in vitro</em>. Oncol Lett 21: 351, 2021.
APA
Chen, Y., Zhao, H., Luo, J., Liao, Y., Tan, K., & Hu, G. (2021). A drug targeting 5‑lipoxygenase enhances the activity of a JAK2 inhibitor in CD34<sup>+</sup> bone marrow cells from patients with JAK2V617F‑positive polycythemia vera <em>in vitro</em>. Oncology Letters, 21, 351. https://doi.org/10.3892/ol.2021.12612
MLA
Chen, Y., Zhao, H., Luo, J., Liao, Y., Tan, K., Hu, G."A drug targeting 5‑lipoxygenase enhances the activity of a JAK2 inhibitor in CD34<sup>+</sup> bone marrow cells from patients with JAK2V617F‑positive polycythemia vera <em>in vitro</em>". Oncology Letters 21.5 (2021): 351.
Chicago
Chen, Y., Zhao, H., Luo, J., Liao, Y., Tan, K., Hu, G."A drug targeting 5‑lipoxygenase enhances the activity of a JAK2 inhibitor in CD34<sup>+</sup> bone marrow cells from patients with JAK2V617F‑positive polycythemia vera <em>in vitro</em>". Oncology Letters 21, no. 5 (2021): 351. https://doi.org/10.3892/ol.2021.12612
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