Efficacy of ALK5 inhibition in myelofibrosis

• DOI: 10.1172/jci.insight.90932
• Publication Date: 2017-04-07T02:24:53Z
• Authors: Lanzhu Yue; Matthias Bartenstein; Wanke Zhao; Wanting Tina Ho; Ying Han; Cem Murdun; Adam W. Mailloux; Ling Zhang; Xuefeng Wang; Anjali Budhathoki; Kith Pradhan; Franck Rapaport; Huaquan Wang; Zonghong Shao; Xiubao Ren; Ulrich Steidl; Ross L. Levine; Zhizhuang Joe Zhao; Amit Verma; Pearlie K. Epling...
• Keywords: Male; 0301 basic medicine; Receptor, Transforming Growth Factor-beta Type I; Cell Differentiation; Mesenchymal Stem Cells; Mice, Transgenic; Janus Kinase 2; Hematopoietic Stem Cells; 3. Good health; Mice, Inbred C57BL; Mice; 03 medical and health sciences; HEK293 Cells; Bone Marrow; Primary Myelofibrosis; Quinolines; Animals; Humans; Pyrazoles; Collagen; Megakaryocytes; Cells, Cultured; Cell Proliferation

Myelofibrosis (MF) is a bone marrow disorder characterized by clonal myeloproliferation, aberrant cytokine production, extramedullary hematopoiesis, and bone marrow fibrosis. Although somatic mutations in JAK2, MPL, and CALR have been identified in the pathogenesis of these diseases, inhibitors of the Jak2 pathway have not demonstrated efficacy in ameliorating MF in patients. TGF-β family members are profibrotic cytokines and we observed significant TGF-β1 isoform overexpression in a large cohort of primary MF patient samples. Significant overexpression of TGF-β1 was also observed in murine clonal MPLW515L megakaryocytic cells. TGF-β1 stimulated the deposition of excessive collagen by mesenchymal stromal cells (MSCs) by activating the TGF-β receptor I kinase (ALK5)/Smad3 pathway. MSCs derived from MPLW515L mice demonstrated sustained overproduction of both collagen I and collagen III, effects that were abrogated by ALK5 inhibition in vitro and in vivo. Importantly, use of galunisertib, a clinically active ALK5 inhibitor, significantly improved MF in both MPLW515L and JAK2V617F mouse models. These data demonstrate the role of malignant hematopoietic stem cell (HSC)/TGF-β/MSC axis in the pathogenesis of MF, and provide a preclinical rationale for ALK5 blockade as a therapeutic strategy in MF.