Abstract
Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by hematopoietic stem-cell-derived clonal proliferation, leading to bone marrow (BM) fibrosis. Hematopoiesis alterations are closely associated with modifications of the BM microenvironment, characterized by defective interactions between vascular and endosteal niches. As such, neoangiogenesis, megakaryocytes hyperplasia and extensive bone marrow fibrosis, followed by osteosclerosis and bone damage, are the most relevant consequences of PMF. Moreover, bone tissue deposition, together with progressive fibrosis, represents crucial mechanisms of disabilities in patients. Although the underlying mechanisms of bone damage observed in PMF are still unclear, the involvement of cytokines, growth factors and bone marrow microenvironment resident cells have been linked to disease progression. Herein, we focused on the role of megakaryocytes and their alterations, associated with cytokines and chemokines release, in modulating functions of most of the bone marrow cell populations and in creating a complex network where impaired signaling strongly contributes to progression and disabilities.
Highlights
primary myelofibrosis (PMF) is a myeloproliferative syndrome with a very complex clinical background, characterized by general bone marrow failure with impaired hematopoiesis followed by extramedullary hematopoiesis, splenomegaly and progressive bone deposition replacing
Conclusions characterized by general bone marrow failure with impaired hematopoiesis followed by extramedullary hematopoiesis, splenomegaly and progressive bone deposition replacing the fibrotic areas
Assuming that the physiological state of bone marrow is based on the continuous balance between the hematopoietic niche and bone remodeling, it is necessary to evaluate the most important factors involved in bone impairment and osteosclerosis
Summary
From a genetic point of view, the vast majority of patients show the JAK2V617F driver mutation; the remaining population of patients usually shows either calreticulin (CALR) mutations or thrombopoietin receptor mutations (i.e., myeloproliferative leukemia, MPL) [1,2,3,4] These mutations could be associated with concomitant mutations to other genes such as ASXL1, IDH1/2, Biomolecules 2021, 11, 122. The main mutations show similarity in the constitutive activation of JAK/STAT signaling This overactivation represents a critical feature of clonal myelopoiesis in MPNs and the main biochemical pathway involved in the pathogenetic progression of myelofibrosis [8,9], playing a role in malignant expansion and compromising nonclonal hematopoietic bone marrow cell populations [10,11]. Disrupted cell interactions and functional variations of stroma, BM-MSC, megakaryocytes, osteoblasts, endothelium and myofibroblasts culminate in the development of bone marrow damage with an inflammatory and profibrotic environment [7]
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