Abstract
Primary myelofibrosis (PMF) is a Ph‐negative myeloproliferative neoplasm (MPN), characterized by advanced bone marrow fibrosis and extramedullary haematopoiesis. The bone marrow fibrosis results from excessive proliferation of fibroblasts that are influenced by several cytokines in the microenvironment, of which transforming growth factor‐β (TGF‐β) is the most important. Micromechanics related to the niche has not yet been elucidated. In this study, we hypothesized that mechanical stress modulates TGF‐β signalling leading to further activation and subsequent proliferation and invasion of bone marrow fibroblasts, thus showing the important role of micromechanics in the development and progression of PMF, both in the bone marrow and in extramedullary sites. Using three PMF‐derived fibroblast cell lines and transforming growth factor‐β receptor (TGFBR) 1 and 2 knock‐down PMF‐derived fibroblasts, we showed that mechanical stress does stimulate the collagen synthesis by the fibroblasts in patients with myelofibrosis, through the TGFBR1, which however seems to be activated through alternative pathways, other than TGFBR2.
Highlights
Primary myelofibrosis (PMF) is a Ph-negative myeloproliferative neoplasm (MPN), characterized by advanced bone marrow fibrosis and extramedullary haematopoiesis that is most pronounced in the liver and spleen.[1]
Using three PMF-derived fibroblast cell lines and transforming growth factor-β receptor (TGFBR) 1 and 2 knock-down PMF-derived fibroblasts, we showed that mechanical stress does stimulate the collagen synthesis by the fibroblasts in patients with myelofibrosis, through the TGFBR1, which seems to be activated through alternative pathways, other than TGFBR2
Several ‘driver’ mutations have been identified in the pathogenesis of PMF, involving target genes such as JAK2, CALR and MPL, whereas less commonly involved genes include ASXL1, SRSF1 and U2AF1.[5,6,7,8] The bone marrow fibrosis results from proliferation of fibroblasts that are influenced by several cytokines in the microenvironment including transforming growth factor-β (TGF β), basic fibroblast growth factor (FGF), platelet-derived growth factor (PDGF) and calmodulin.[9,10,11,12,13]
Summary
Primary myelofibrosis (PMF) is a Ph-negative myeloproliferative neoplasm (MPN), characterized by advanced bone marrow fibrosis and extramedullary haematopoiesis that is most pronounced in the liver and spleen.[1]. The main cytokine believed to be involved in generation of PMFassociated fibrosis is TGF β.[17] TGF-β acts on fibroblast physiology by increasing synthesis of collagen, type I, III, IV and V, as well as production of fibronectin, proteoglycans and tenascin.[18] the importance of TGF β in fibroblast proliferation was previously underlined in studies of PMF, micromechanics related to the niche has yet been elucidated, as progression in PMF occurs in a tense niche, with a relatively high level of mechanical stress.[18,19] The role of bone marrow mechanical stress via TGF-β modulation was assessed by Balooch et al, with potential clinical implications.[20] Data were confirmed by Zhao et al[21] that have shown that bone marrow-derived mesenchymal stem cells have resistance to flow shear stress through AMP-activated protein kinase signalling.
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