The role of growth differentiation factor 15 in the pathogenesis of primary myelofibrosis

Cancer Medicine

Tatsuki Uchiyama²  Hiroshi Kawabata²  Yasuo Miura³  Satoshi Yoshioka²  Masaki Iwasa³  Hisayuki Yao³  Soichiro Sakamoto²  Masakazu Fujimoto¹  Hironori Haga¹  Norimitsu Kadowaki²  Taira Maekawa³ 

[1] Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan;Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan;Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Kyoto, Japan

关键词: Growth differentiation factor 15;    osteoblastic differentiation;    primary myelofibrosis;   

DOI  :  10.1002/cam4.502

来源: Wiley

【 摘 要 】

Abstract

Growth differentiation factor 15 (GDF15) is a pleiotropic cytokine that belongs to the transforming growth factor-β superfamily. Elevated serum concentrations of this cytokine have been reported in patients with various malignancies. To assess the potential roles of GDF15 in hematologic malignancies, we measured its serum levels in patients with these diseases. We found that serum GDF15 levels were elevated in almost all these patients, particularly in patients with primary myelofibrosis (PMF). Immunohistochemical staining of bone marrow (BM) specimens revealed that GDF15 was strongly expressed by megakaryocytes, which may be sources of increased serum GDF15 in PMF patients. Therefore, we further assessed the contribution of GDF15 to the pathogenesis of PMF. Recombinant human (rh) GDF15 enhanced the growth of human BM mesenchymal stromal cells (BM-MSCs), and it enhanced the potential of these cells to support human hematopoietic progenitor cell growth in a co-culture system. rhGDF15 enhanced the growth of human primary fibroblasts, but it did not affect their expression of profibrotic genes. rhGDF15 induced osteoblastic differentiation of BM-MSCs in vitro, and pretreatment of BM-MSCs with rGDF15 enhanced the induction of bone formation in a xenograft mouse model. These results suggest that serum levels of GDF15 in PMF are elevated, that megakaryocytes are sources of this cytokine in BM, and that GDF15 may modulate the pathogenesis of PMF by enhancing proliferation and promoting osteogenic differentiation of BM-MSCs.

【 授权许可】

CC BY   
© 2015 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

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