Genetic studies reveal an unexpected negative regulatory role for Jak2 in thrombopoiesis.

Blood 2014 Oct 12;124(14):2280-4. Epub 2014 Aug 12.

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.

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.

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Source
http://dx.doi.org/10.1182/blood-2014-03-560441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4183987PMC
October 2014

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