Brief Report PLATELETS AND THROMBOPOIESIS Genetic studies reveal an unexpected negative regulatory role for Jak2 in thrombopoiesis

• Jak2 deletion in PLTs and MKs leads to thrombocytosis due to dysregulated TPO turnover. • Jak2 loss in PLTs/MKs induces non-autonomous expansion of stem/progenitors, and specifically of MK-primed hematopoietic stem cells (HSCs). 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, andJak-Stat signaling.Pf4-Cre–mediatedJak2deletion inPLTsandMKs did not compromise PLT formation but caused thrombocytosis, and resulted in expansion ofMKprogenitors andLinSca1Kitcells. Serumthrombopoietin (TPO)wasmaintained at normal levels in Pf4-Cre–positive Jak2 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 andMKs, but rather due to JAK2 inhibition in stem/progenitor cells. (Blood. 2014;124(14):2280-2284)