Journal article
Efficacy of ALK5 inhibition in myelofibrosis
JCI insight, Vol.2(7), pp.e90932-e90932
04/06/2017
DOI: 10.1172/jci.insight.90932
PMCID: PMC5374075
PMID: 28405618
Abstract
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-beta family members are profibrotic cytokines and we observed significant TGF-beta 1 isoform overexpression in a large cohort of primary MF patient samples. Significant overexpression of TGF-beta 1 was also observed in murine clonal MPLW515L megakaryocytic cells. TGF-beta 1 stimulated the deposition of excessive collagen by mesenchymal stromal cells (MSCs) by activating the TGF-beta 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 JAK2(V617F) mouse models. These data demonstrate the role of malignant hematopoietic stem cell (HSC)/TGF-beta/MSC axis in the pathogenesis of MF, and provide a preclinical rationale for ALK5 blockade as a therapeutic strategy in MF.
Details
- Title: Subtitle
- Efficacy of ALK5 inhibition in myelofibrosis
- Creators
- Lanzhu Yue - Moffitt Cancer CenterMatthias Bartenstein - Albert Einstein College of MedicineWanke Zhao - University of Oklahoma Health Sciences CenterWanting Tina Ho - University of Oklahoma Health Sciences CenterYing Han - Tianjin Medical UniversityCem Murdun - Moffitt Cancer CenterAdam W. Mailloux - Moffitt Cancer CenterLing Zhang - Department of Hematopathology and Laboratory Medicine.Xuefeng Wang - Moffitt Cancer CenterAnjali Budhathoki - Albert Einstein College of MedicineKith Pradhan - Albert Einstein College of MedicineFranck Rapaport - Memorial Sloan Kettering Cancer CenterHuaquan Wang - Tianjin Medical University General HospitalZonghong Shao - Tianjin Medical University General HospitalXiubao Ren - Tianjin Medical University Cancer Institute and HospitalUlrich Steidl - Albert Einstein College of MedicineRoss L. Levine - Memorial Sloan Kettering Cancer CenterZhizhuang Joe Zhao - University of Oklahoma Health Sciences CenterAmit Verma - Albert Einstein College of MedicinePearlie K. Epling-Burnette - Moffitt Cancer Center
- Resource Type
- Journal article
- Publication Details
- JCI insight, Vol.2(7), pp.e90932-e90932
- Publisher
- Amer Soc Clinical Investigation Inc
- DOI
- 10.1172/jci.insight.90932
- PMID
- 28405618
- PMCID
- PMC5374075
- ISSN
- 0021-9738
- eISSN
- 2379-3708
- Number of pages
- 15
- Grant note
- I01CX000114 / Veterans Affairs; US Department of Veterans Affairs P30CA076292 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) MPN Foundation and Leukemia Lymphoma Society P30-CA076292 / Biostatistics Core Facility Gottesman Stem Institute
- Language
- English
- Date published
- 04/06/2017
- Academic Unit
- Microbiology and Immunology
- Record Identifier
- 9984297322702771
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