Genetic ablation of Pim1 or pharmacologic inhibition with TP-3654 ameliorates myelofibrosis in murine models

• Published in: Leukemia 2022-03, Vol.36 (3), p.746-759
• Main Authors: Dutta, Avik, Nath, Dipmoy, Yang, Yue, Le, Bao T., Rahman, Mohammad Ferdous-Ur, Faughnan, Patrick, Wang, Zhenjia, Stuver, Matthew, He, Rongquan, Tan, Wuwei, Hutchison, Robert E., Foulks, Jason M., Warner, Steven L., Zang, Chongzhi, Mohi, Golam
• Format: Article
• Language: English
• Subjects: 13/95; 45/91; 631/67/1990/2331; 64/60; 692/699/1541/1990/2331; 82/51; 96/31; 96/63; Ablation; Animal models; Animals; Bone marrow; Cancer Research; Cell Line; Combined treatment; Critical Care Medicine; Disease Models, Animal; Enzyme inhibitors; Fibrosis; Gene Deletion; Hematology; Hemopoiesis; Humans; Intensive; Internal Medicine; Janus Kinase 2 - genetics; Kinases; Leukocytes; Leukocytosis; Medicine; Medicine & Public Health; Mice; Mice, Knockout; Mutants; Myc protein; Myelofibrosis; Oncology; Pathogenesis; Pharmacology; Primary Myelofibrosis - drug therapy; Primary Myelofibrosis - genetics; Progenitor cells; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Proto-Oncogene Proteins c-pim-1 - antagonists & inhibitors; Proto-Oncogene Proteins c-pim-1 - genetics; Spleen; Splenomegaly
• ISSN: 0887-6924; 1476-5551; 1476-5551
• DOI: 10.1038/s41375-021-01464-2

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.