Mpl Expression on Megakaryocytes and Platelets is Dispensable for Thrombopoiesis but Essential to Prevent Myeloproliferation

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2014 Apr 9

PMID 24711413

Citations 58

Authors

Ashley P Ng

Maria Kauppi

Donald Metcalf

Craig D Hyland

Emma C Josefsson

Marion Lebois

Jian-Guo Zhang

Tracey M Baldwin

Ladina Di Rago

Douglas J Hilton

Warren S Alexander

Affiliations

Soon will be listed here.

Abstract

Thrombopoietin (TPO) acting via its receptor, the cellular homologue of the myeloproliferative leukemia virus oncogene (Mpl), is the major cytokine regulator of platelet number. To precisely define the role of specific hematopoietic cells in TPO-dependent hematopoiesis, we generated mice that express the Mpl receptor normally on stem/progenitor cells but lack expression on megakaryocytes and platelets (Mpl(PF4cre/PF4cre)). Mpl(PF4cre/PF4cre) mice displayed profound megakaryocytosis and thrombocytosis with a remarkable expansion of megakaryocyte-committed and multipotential progenitor cells, the latter displaying biological responses and a gene expression signature indicative of chronic TPO overstimulation as the underlying causative mechanism, despite a normal circulating TPO level. Thus, TPO signaling in megakaryocytes is dispensable for platelet production; its key role in control of platelet number is via generation and stimulation of the bipotential megakaryocyte precursors. Nevertheless, Mpl expression on megakaryocytes and platelets is essential to prevent megakaryocytosis and myeloproliferation by restricting the amount of TPO available to stimulate the production of megakaryocytes from the progenitor cell pool.

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