title: The thrombopoietin receptor, MPL, is critical for development of a JAK2V617F-induced myeloproliferative neoplasm.
abstract: The most frequent contributing factor in Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) is the acquisition of a V617F mutation in Janus kinase 2 (JAK2) in hematopoietic stem cells (HSCs). Recent evidence has demonstrated that to drive MPN transformation, JAK2V617F needs to directly associate with a functional homodimeric type I cytokine receptor, suggesting that, although acquiring JAK2V617F may promote disease, there are additional cellular components necessary for MPN development. Here we show that loss of the thrombopoietin (TPO) receptor (MPL) significantly ameliorates MPN development in JAK2V617F(+) transgenic mice, whereas loss of TPO only mildly affects the disease phenotype. Specifically, compared with JAK2V617F(+) mice, JAK2V617F(+)Mpl(-/-) mice exhibited reduced thrombocythemia, neutrophilia, splenomegaly, and neoplastic stem cell pool. The importance of MPL is highlighted as JAK2V617FMpl(+/-) mice displayed a significantly reduced MPN phenotype, indicating that Mpl level may have a substantial effect on MPN development and severity. Splenomegaly and the increased neoplastic stem cell pool were retained in JAK2V617F(+)Tpo(-/-) mice, although thrombocytosis was reduced compared with JAK2V617F(+) mice. These results demonstrate that Mpl expression, but not Tpo, is fundamental in the development of JAK2V617F(+) MPNs, highlighting an entirely novel target for therapeutic intervention.
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, NY; Centre for Immunology and Infection, Department Biology, and.
authors.forename: Veena
authors.initials: V
authors.lastname: Sangkhae
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, NY; Department of Biology, University of York, Heslington Campus, York, United Kingdom.
authors.forename: S Leah
authors.initials: SL
authors.lastname: Etheridge
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, NY;
authors.forename: Kenneth
authors.initials: K
authors.lastname: Kaushansky
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, NY; Centre for Immunology and Infection, Department Biology, and.
authors.forename: Ian S
authors.initials: IS
authors.lastname: Hitchcock
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006579:Heterozygote; D006720:Homozygote; D053614:Janus Kinase 2 / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009196:Myeloproliferative Disorders / Q000378:metabolism*; D053628:Receptors, Thrombopoietin / Q000235:genetics* / Q000502:physiology; D013234:Stem Cells / Q000166:cytology
chemical_list: D016207:Cytokines; C481270:Mpl protein, mouse; D053628:Receptors, Thrombopoietin; C082218:MPL protein, human; C507924:JAK2 protein, human; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2