JAK2V617F Megakaryocytes Promote Hematopoietic Stem/Progenitor Cell Expansion in Mice Through Thrombopoietin/MPL Signaling

Stem Cells
Yu ZhangHuichun Zhan

Abstract

The myeloproliferative neoplasms (MPNs) are stem cell disorders characterized by hematopoietic stem/progenitor cell (HSPC) expansion and overproduction of mature blood cells. The acquired kinase mutation JAK2V617F plays a central role in these disorders. The mechanisms responsible for HSPC expansion in MPNs are not fully understood, limiting the effectiveness of current treatments. One hallmark feature of the marrow in patients with MPNs is megakaryocyte (MK) hyperplasia. Previously, we reported that JAK2V617F-bearing MKs cause a murine myeloproliferative syndrome with HSPC expansion. Here we show that JAK2V617F MKs promote MPN stem cell function by inducing HSPC quiescence with increased repopulating capacity. In addition, we demonstrate that thrombopoietin and its receptor MPL are critical for the JAK2V617F-bearing MK-induced myeloproliferation, both by directly affecting the quantity and quality of MKs and by altering the MK-endothelial interaction and vascular niche function. Therefore, targeting HSPC niche-forming MKs and/or their interactions within the vascular niche could provide novel, more effective therapeutic strategies in patients with MPNs. Stem Cells 2018;36:1676-1684.

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Citations

Oct 15, 2019·British Journal of Haematology·Chia-Chen HsuChih-Cheng Chen
Jun 21, 2019·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Brittany WoodsQiang Jeremy Wen
Dec 18, 2020·Frontiers in Immunology·Vasundhara SharmaGary W Reuther
Nov 3, 2020·HemaSphere·Miriam BelmonteDavid G Kent
May 10, 2021·Current Opinion in Hematology·Joydeep GhoshEdward F Srour
Jul 8, 2021·Current Opinion in Hematology·Hélène F E GleitzRebekka K Schneider
Jan 28, 2022·Blood Cancer Journal·Garima PandeyGary W Reuther

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