TY - JOUR
T1 - Efficacy of ALK5 inhibition in myelofibrosis
AU - Yue, Lanzhu
AU - Bartenstein, Matthias
AU - Zhao, Wanke
AU - Ho, Wanting Tina
AU - Han, Ying
AU - Murdun, Cem
AU - Mailloux, Adam W.
AU - Zhang, Ling
AU - Wang, Xuefeng
AU - Budhathoki, Anjali
AU - Pradhan, Kith
AU - Rapaport, Franck
AU - Wang, Huaquan
AU - Shao, Zonghong
AU - Ren, Xiubao
AU - Steidl, Ulrich
AU - Levine, Ross L.
AU - Zhao, Zhizhuang Joe
AU - Verma, Amit
AU - Epling-Burnette, Pearlie K.
N1 - Publisher Copyright:
© 2017 American Society for Clinical Investigation. All rights reserved.
PY - 2021/4/6
Y1 - 2021/4/6
N2 - 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.
AB - 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.
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U2 - 10.1172/jci.insight.90932
DO - 10.1172/jci.insight.90932
M3 - Article
C2 - 28405618
AN - SCOPUS:85043508838
SN - 0021-9738
VL - 2
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 7
M1 - e90932
ER -