title: Efficacy of ALK5 inhibition in myelofibrosis.
abstract: Myelofibrosis (MF) is a bone marrow disorder characterized by clonal myeloproliferation, aberrant cytokine production, extramedullary hematopoiesis, and bone marrow fibrosis. Although somatic mutations inJAK2,MPL, andCALRhave 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 clonalMPLW515Lmegakaryocytic 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 fromMPLW515Lmice 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 bothMPLW515LandJAK2V617Fmouse 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.
authors.affiliation: Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.|Department of Hematology, Tianjin Medical University General Hospital, Tianjin, China.
authors.forename: Lanzhu
authors.initials: L
authors.lastname: Yue
authors.affiliation: Department of Oncology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York, USA.
authors.forename: Matthias
authors.initials: M
authors.lastname: Bartenstein
authors.affiliation: Department of Pathology, Peggy and Stephenson Cancer Center, Oklahoma University Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Wanke
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Department of Pathology, Peggy and Stephenson Cancer Center, Oklahoma University Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Wanting Tina
authors.initials: WT
authors.lastname: Ho
authors.affiliation: Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.|Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Immunology and Biotherapy, Key Laboratory of Cancer Prevention and Therapy, Tianjin, PR China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Han
authors.affiliation: Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
authors.forename: Cem
authors.initials: C
authors.lastname: Murdun
authors.affiliation: Translational Science, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
authors.forename: Adam W
authors.initials: AW
authors.lastname: Mailloux
authors.affiliation: Department of Hematopathology and Laboratory Medicine.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Oncology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York, USA.
authors.forename: Anjali
authors.initials: A
authors.lastname: Budhathoki
authors.affiliation: Department of Oncology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York, USA.
authors.forename: Kith
authors.initials: K
authors.lastname: Pradhan
authors.affiliation: Leukemia Center, Memorial Sloan Kettering Cancer Center, New York City, New York, USA.
authors.forename: Franck
authors.initials: F
authors.lastname: Rapaport
authors.affiliation: Department of Hematology, Tianjin Medical University General Hospital, Tianjin, China.
authors.forename: Huaquan
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Hematology, Tianjin Medical University General Hospital, Tianjin, China.
authors.forename: Zonghong
authors.initials: Z
authors.lastname: Shao
authors.affiliation: Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Immunology and Biotherapy, Key Laboratory of Cancer Prevention and Therapy, Tianjin, PR China.
authors.forename: Xiubao
authors.initials: X
authors.lastname: Ren
authors.affiliation: Department of Oncology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York, USA.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Steidl
authors.affiliation: Leukemia Center, Memorial Sloan Kettering Cancer Center, New York City, New York, USA.
authors.forename: Ross L
authors.initials: RL
authors.lastname: Levine
authors.affiliation: Department of Pathology, Peggy and Stephenson Cancer Center, Oklahoma University Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Zhizhuang Joe
authors.initials: ZJ
authors.lastname: Zhao
authors.affiliation: Department of Oncology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Verma
authors.affiliation: Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
authors.forename: Pearlie K
authors.initials: PK
authors.lastname: Epling-Burnette
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D057809:HEK293 Cells; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D053614:Janus Kinase 2 / Q000378:metabolism*; D008297:Male; D008533:Megakaryocytes / Q000378:metabolism / Q000473:pathology; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D055728:Primary Myelofibrosis / Q000188:drug therapy* / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D000077293:Receptor, Transforming Growth Factor-beta Type I / Q000037:antagonists & inhibitors*; D053628:Receptors, Thrombopoietin / Q000378:metabolism*; D015398:Signal Transduction; D051900:Smad3 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: C481270:Mpl protein, mouse; D011720:Pyrazoles; D011804:Quinolines; D053628:Receptors, Thrombopoietin; D051900:Smad3 Protein; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; C557799:LY-2157299; D003094:Collagen; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625842:Tgfbr1 protein, mouse