Open AccessGenetic ablation of Pim1 or pharmacologic inhibition with TP-3654 ameliorates myelofibrosis in murine models
Author(s) -
Avik Dutta,
Dipmoy Nath,
Yue Yang,
Bao T. Le,
Mohammad Ferdous-Ur Rahman,
Patrick Faughnan,
Zhenjia Wang,
Matthew Stuver,
RongQuan He,
Wuwei Tan,
Robert Hutchison,
Jason M. Foulks,
Steven L. Warner,
Chongzhi Zang,
Golam Mohi
Publication year - 2021
Publication title -
leukemia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.539
H-Index - 192
eISSN - 1476-5551
pISSN - 0887-6924
DOI - 10.1038/s41375-021-01464-2
Subject(s) - ruxolitinib , myelofibrosis , pim1 , bone marrow , haematopoiesis , myeloproliferative neoplasm , biology , cancer research , granulocytosis , immunology , fibrosis , medicine , stem cell , granulocyte , genetics , phosphorylation , serine
Myelofibrosis (MF) is the deadliest form of myeloproliferative neoplasm (MPN). The JAK inhibitor Ruxolitinib can reduce constitutional symptoms but it does not substantially improve bone marrow fibrosis. Pim1 expression is significantly elevated in MPN/MF hematopoietic progenitors. Here, 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 and 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. Mechanistically, we show that TP-3654 treatment significantly inhibits mTORC1, MYC and TGF-β signaling in Jak2V617F mutant hematopoietic cells and diminishes the expression of fibrotic markers in the bone marrow. Collectively, 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.