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Chronic myleproliferative neoplasms

Deletion of Stat3 enhances myeloid cell expansion and increases the severity of myeloproliferative neoplasms in Jak2V617F knock-in mice

Leukemia volume 29, pages 2050–2061 (2015)Cite this article

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Abstract

The JAK2V617F mutation commonly found in myeloproliferative neoplasms (MPNs) induces constitutive phosphorylation/activation of the signal transducer and activator of transcription 3 (Stat3). However, the contribution of Stat3 in MPN evoked by JAK2V617F remains unknown. To determine the role of Stat3 in JAK2V617F-induced MPN, we generated Stat3-deficient Jak2V617F-expressing mice. Whereas expression of Jak2V617F resulted in a polycythemia vera-like disease characterized by increased red blood cells (RBCs), hematocrit, neutrophils and platelets in the peripheral blood of Jak2V617F knock-in mice, deletion of Stat3 slightly reduced RBC and hematocrit parameters and modestly increased platelet numbers in Jak2V617F knock-in mice. Moreover, deletion of Stat3 significantly increased the neutrophil counts/percentages and markedly reduced the survival of mice expressing Jak2V617F. These phenotypic manifestations were reproduced upon bone marrow (BM) transplantation into wild-type animals. Flow cytometric analysis showed increased hematopoietic stem cell and granulocyte-macrophage progenitor populations in the BM and spleens of Stat3-deficient Jak2V617F mice. Stat3 deficiency also caused a marked expansion of Gr-1+/Mac-1+ myeloid cells in Jak2V617F knock-in mice. Histopathologic analysis revealed marked increase in granulocytes in the BM, spleens and livers of Stat3-deficient Jak2V617F-expressing mice. Together, these results suggest that deletion of Stat3 increases the severity of MPN induced by Jak2V617F.

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Acknowledgements

We thank Dr Valeria Poli (University of Turin, Italy) for providing the Stat3-floxed mouse. This work was supported by the grants from the Leukemia and Lymphoma Society and US National Institute of Health (NIH; R01 HL095685) awarded to GM. GM is a scholar of the Leukemia and Lymphoma Society.

Author Contributions

DY performed research, analyzed data and wrote the manuscript; FJ performed research; REH performed histopathologic analysis and revised the manuscript; GM designed the research, analyzed data and wrote the manuscript.

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Authors and Affiliations

  1. Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY, USA

    D Yan, F Jobe & G Mohi

  2. Department of Pathology, SUNY Upstate Medical University, Syracuse, NY, USA

    R E Hutchison

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  1. D Yan
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Correspondence to G Mohi.

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Yan, D., Jobe, F., Hutchison, R. et al. Deletion of Stat3 enhances myeloid cell expansion and increases the severity of myeloproliferative neoplasms in Jak2V617F knock-in mice. Leukemia 29, 2050–2061 (2015). https://doi.org/10.1038/leu.2015.116

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