Mpl expression on megakaryocytes and platelets is dispensable for thrombopoiesis but essential to prevent myeloproliferation.
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.
Divisions of Cancer and Haematology, and Molecular Medicine, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
Ashley P
AP
Ng
Maria
M
Kauppi
Donald
D
Metcalf
Craig D
CD
Hyland
Emma C
EC
Josefsson
Marion
M
Lebois
Jian-Guo
JG
Zhang
Tracey M
TM
Baldwin
Ladina
L
Di Rago
Douglas J
DJ
Hilton
Warren S
WS
Alexander
D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D001792:Blood Platelets / Q000166:cytology / Q000378:metabolism*; D002451:Cell Compartmentation; D049109:Cell Proliferation; D002999:Clone Cells; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D018390:Gene Targeting; D056426:Genetic Loci / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D019426:Integrases / Q000378:metabolism; D008533:Megakaryocytes / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D022423:Myeloid Cells / Q000166:cytology* / Q000378:metabolism; D053628:Receptors, Thrombopoietin / Q000378:metabolism*; D013922:Thrombocytosis; D034061:Thrombopoiesis; D013926:Thrombopoietin / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
D018952:Antigens, CD34; C481270:Mpl protein, mouse; D053628:Receptors, Thrombopoietin; D013926:Thrombopoietin; C045073:Cre recombinase; D019426:Integrases
bone marrow; essential thrombocythemia