Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 111, Issue 16, Pages 5884-5889Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1404354111
Keywords
bone marrow; essential thrombocythemia
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Funding
- Australian National Health and Medical Research Council [1016647, 490037, 575501]
- Independent Research Institutes Infrastructure Support Scheme [361646]
- Carden Fellowship of the Cancer Council, Victoria
- Cure Cancer Australia/Leukaemia Foundation Australia Post Doctoral Fellowship
- Lions Fellowship, Cancer Council of Victoria
- Australian Cancer Research Fund
- Victorian State Government
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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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