title: Genetic studies reveal an unexpected negative regulatory role for Jak2 in thrombopoiesis.
abstract: JAK inhibitor treatment is limited by the variable development of anemia and thrombocytopenia thought to be due to on-target JAK2 inhibition. We evaluated the impact of Jak2 deletion in platelets (PLTs) and megakaryocytes (MKs) on blood counts, stem/progenitor cells, and Jak-Stat signaling. Pf4-Cre-mediated Jak2 deletion in PLTs and MKs did not compromise PLT formation but caused thrombocytosis, and resulted in expansion of MK progenitors and Lin(-)Sca1(+)Kit+ cells. Serum thrombopoietin (TPO) was maintained at normal levels in Pf4-Cre-positive Jak2(f/f) mice, consistent with reduced internalization/turnover by Jak2-deficient PLTs. These data demonstrate that Jak2 in terminal megakaryopoiesis is not required for PLT production, and that Jak2 loss in PLTs and MKs results in non-autonomous expansion of stem/progenitors and of MKs and PLTs via dysregulated TPO turnover. This suggests that the thrombocytopenia frequently seen with JAK inhibitor treatment is not due to JAK2 inhibition in PLTs and MKs, but rather due to JAK2 inhibition in stem/progenitor cells.
authors.affiliation: Human Oncology and Pathogenesis Program.
authors.forename: Sara C
authors.initials: SC
authors.lastname: Meyer
authors.affiliation: Human Oncology and Pathogenesis Program.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Keller
authors.affiliation: Human Oncology and Pathogenesis Program, Gerstner Sloan Kettering School of Biomedical Sciences, and.
authors.forename: Brittany A
authors.initials: BA
authors.lastname: Woods
authors.affiliation: Human Oncology and Pathogenesis Program, Gerstner Sloan Kettering School of Biomedical Sciences, and.
authors.forename: Lindsay M
authors.initials: LM
authors.lastname: LaFave
authors.affiliation: Human Oncology and Pathogenesis Program.
authors.forename: Lennart
authors.initials: L
authors.lastname: Bastian
authors.affiliation: Human Oncology and Pathogenesis Program.
authors.forename: Maria
authors.initials: M
authors.lastname: Kleppe
authors.affiliation: Human Oncology and Pathogenesis Program, Gerstner Sloan Kettering School of Biomedical Sciences, and.
authors.forename: Neha
authors.initials: N
authors.lastname: Bhagwat
authors.affiliation: Human Oncology and Pathogenesis Program.
authors.forename: Sachie
authors.initials: S
authors.lastname: Marubayashi
authors.affiliation: Human Oncology and Pathogenesis Program, Gerstner Sloan Kettering School of Biomedical Sciences, and Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Ross L
authors.initials: RL
authors.lastname: Levine
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000166:cytology; D003433:Crosses, Genetic; D017353:Gene Deletion; D015971:Gene Expression Regulation, Enzymologic; D006412:Hematopoietic Stem Cells / Q000166:cytology; D053614:Janus Kinase 2 / Q000235:genetics* / Q000378:metabolism*; D008533:Megakaryocytes / Q000166:cytology; D051379:Mice; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology; D013922:Thrombocytosis / Q000378:metabolism*; D034061:Thrombopoiesis / Q000502:physiology*; D013926:Thrombopoietin / Q000097:blood / Q000378:metabolism
chemical_list: D013926:Thrombopoietin; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2