Interferon-α targets JAK2V617F-positive hematopoietic progenitor cells and acts through the p38 MAPK pathway

Min Lu, Wei Zhang, Yan Li, Dmitriy Berenzon, Xiaoli Wang, Jiapeng Wang, John Mascarenhas, Mingjiang Xu, Ronald Hoffman

Research output: Contribution to journalArticle

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Abstract

Objective: Interferon-α (IFNα) therapy leads to hematological remissions and a reduction of the JAK2V617F allele burden in patients with polycythemia vera (PV). In this study, the cellular target by which IFNα affects hematopoiesis in PV patients was evaluated. Materials and Methods: CD34+ cells were isolated from normal bone marrow and the peripheral blood of patients with PV and were treated in vitro with each of the three commercially available forms of IFNα: IFNα 2b, pegylated IFNα 2a (Peg-IFNα 2a), and pegylated IFNα 2b (Peg-IFNα 2b). Results: Each form of IFNα was equally potent in suppressing hematopoietic colony formation by normal CD34+ cells, but Peg-IFNα 2a and IFNα 2b were more effective than Peg-IFNα 2b in inhibiting burst-forming unit erythroid-derived colony formation by PV CD34+ cells. In addition, exposure of PV CD34+ cells to equal doses of Peg-IFNα 2a and IFNα 2b resulted in a 38% to 40% reduction in the proportion of JAK2V617F-positive hematopoietic progenitor cells (HPC), while equivalent doses of Peg-IFNα 2b did not reduce the number of malignant HPC. Further studies explored the mechanism by which IFNα induced PV HPC growth inhibition. Treatment of Peg-IFNα 2a increased the rate of apoptosis of PV CD34+ cells and the phosphorylation/activation of p38 mitogen-activated protein kinase in PV CD34+ cells, while the p38-specific inhibitor SB203580 reversed the growth inhibition and apoptosis induced by Peg-IFNα 2a. Conclusion: These data suggest that low doses of IFNα selectively and directly suppress PV JAK2V617F HPC and that these agents act through the p38 mitogen-activated protein kinase pathway.

Original languageEnglish (US)
Pages (from-to)472-480
Number of pages9
JournalExperimental Hematology
Volume38
Issue number6
DOIs
StatePublished - Jun 2010
Externally publishedYes

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p38 Mitogen-Activated Protein Kinases
Hematopoietic Stem Cells
Polycythemia Vera
Interferons
Apoptosis
Erythroid Precursor Cells
Hematopoiesis
Growth
Bone Marrow
Alleles
Phosphorylation

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Genetics
  • Molecular Biology
  • Hematology

Cite this

Interferon-α targets JAK2V617F-positive hematopoietic progenitor cells and acts through the p38 MAPK pathway. / Lu, Min; Zhang, Wei; Li, Yan; Berenzon, Dmitriy; Wang, Xiaoli; Wang, Jiapeng; Mascarenhas, John; Xu, Mingjiang; Hoffman, Ronald.

In: Experimental Hematology, Vol. 38, No. 6, 06.2010, p. 472-480.

Research output: Contribution to journalArticle

Lu, M, Zhang, W, Li, Y, Berenzon, D, Wang, X, Wang, J, Mascarenhas, J, Xu, M & Hoffman, R 2010, 'Interferon-α targets JAK2V617F-positive hematopoietic progenitor cells and acts through the p38 MAPK pathway', Experimental Hematology, vol. 38, no. 6, pp. 472-480. https://doi.org/10.1016/j.exphem.2010.03.005
Lu, Min ; Zhang, Wei ; Li, Yan ; Berenzon, Dmitriy ; Wang, Xiaoli ; Wang, Jiapeng ; Mascarenhas, John ; Xu, Mingjiang ; Hoffman, Ronald. / Interferon-α targets JAK2V617F-positive hematopoietic progenitor cells and acts through the p38 MAPK pathway. In: Experimental Hematology. 2010 ; Vol. 38, No. 6. pp. 472-480.
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AU - Lu, Min

AU - Zhang, Wei

AU - Li, Yan

AU - Berenzon, Dmitriy

AU - Wang, Xiaoli

AU - Wang, Jiapeng

AU - Mascarenhas, John

AU - Xu, Mingjiang

AU - Hoffman, Ronald

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