Dataset Information

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 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-? family members are profibrotic cytokines and we observed significant TGF-?1 isoform overexpression in a large cohort of primary MF patient samples. Significant overexpression of TGF-?1 was also observed in murine clonal MPL^W515L megakaryocytic cells. TGF-?1 stimulated the deposition of excessive collagen by mesenchymal stromal cells (MSCs) by activating the TGF-? receptor I kinase (ALK5)/Smad3 pathway. MSCs derived from MPL^W515L 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 MPL^W515L and JAK2^V617F mouse models. These data demonstrate the role of malignant hematopoietic stem cell (HSC)/TGF-?/MSC axis in the pathogenesis of MF, and provide a preclinical rationale for ALK5 blockade as a therapeutic strategy in MF.

SUBMITTER: Yue L

PROVIDER: S-EPMC5374075 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Efficacy of ALK5 inhibition in myelofibrosis.

Yue Lanzhu L Bartenstein Matthias M Zhao Wanke W Ho Wanting Tina WT Han Ying Y Murdun Cem C Mailloux Adam W AW Zhang Ling L Wang Xuefeng X Budhathoki Anjali A Pradhan Kith K Rapaport Franck F Wang Huaquan H Shao Zonghong Z Ren Xiubao X Steidl Ulrich U Levine Ross L RL Zhao Zhizhuang Joe ZJ Verma Amit A Epling-Burnette Pearlie K PK

JCI insight 20170406 7

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 overexpres ...[more]

PMID: 28405618

Similar Datasets

Project description:BackgroundRadiotherapy is widely used to treat cancer. While rapidly dividing cancer cells are naturally considered the main target of radiotherapy, emerging evidence indicates that radiotherapy also affects endothelial cell functions, and possibly also their angiogenic capacity. In spite of its clinical relevance, such putative anti-angiogenic effect of radiotherapy has not been thoroughly characterized. We have investigated the effect of ionizing radiation on angiogenesis using in vivo, ex vivo and in vitro experimental models in combination with genetic and pharmacological interventions.Principal findingsHere we show that high doses ionizing radiation locally suppressed VEGF- and FGF-2-induced Matrigel plug angiogenesis in mice in vivo and prevented endothelial cell sprouting from mouse aortic rings following in vivo or ex vivo irradiation. Quiescent human endothelial cells exposed to ionizing radiation in vitro resisted apoptosis, demonstrated reduced sprouting, migration and proliferation capacities, showed enhanced adhesion to matrix proteins, and underwent premature senescence. Irradiation induced the expression of P53 and P21 proteins in endothelial cells, but p53 or p21 deficiency and P21 silencing did not prevent radiation-induced inhibition of sprouting or proliferation. Radiation induced Smad-2 phosphorylation in skin in vivo and in endothelial cells in vitro. Inhibition of the TGF-beta type I receptor ALK5 rescued deficient endothelial cell sprouting and migration but not proliferation in vitro and restored defective Matrigel plug angiogenesis in irradiated mice in vivo. ALK5 inhibition, however, did not rescue deficient proliferation. Notch signaling, known to hinder angiogenesis, was activated by radiation but its inhibition, alone or in combination with ALK5 inhibition, did not rescue suppressed proliferation.ConclusionsThese results demonstrate that irradiation of quiescent endothelial cells suppresses subsequent angiogenesis and that ALK5 is a critical mediator of this suppression. These results extend our understanding of radiotherapy-induced endothelial dysfunctions, relevant to both therapeutic and unwanted effects of radiotherapy.

Dataset Information

Efficacy of ALK5 inhibition in myelofibrosis.

Publications

Efficacy of ALK5 inhibition in myelofibrosis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets