Effects of Pim1 inhibition with TP-3654 on hematopoietic progenitors of Jak2V617F mice

Myelofibrosis (MF) is the deadliest form of myeloproliferative neoplasm (MPN). Pim1 expression is significantly elevated in MPN/MF hematopoietic progenitors. So, we investigated the role of Pim1 in myelofibrosis. We show that genetic ablation of Pim1 blocked the development of myelofibrosis induced by Jak2V617F and MPLW515L. Pharmacologic inhibition of Pim1 with a second-generation Pim kinase inhibitor TP-3654 significantly reduced leukocytosis, splenomegaly and attenuated bone marrow fibrosis in Jak2V617F and MPLW515L mouse models of MF. Combined treatment of TP-3654 and Ruxolitinib resulted in greater reduction of spleen size, normalization of blood leukocyte counts and abrogation of bone marrow fibrosis in murine models of MF. TP-3654 treatment also preferentially inhibited Jak2V617F mutant hematopoietic progenitors in mice. Our results suggest that Pim1 plays an important role in the pathogenesis of MF, and inhibition of Pim1 with TP-3654 might be useful for treatment of MF. RNA sequencing analysis was performed on sorted LSK cells from Mx1Cre; Jak2VF/VF mice treated with vehicle or TP-3654 (150 mg/kg/day) for 6 weeks. There are three biological replicates for each treatment group and six samples in total.