Role of neoplastic monocyte-derived fibrocytes in primary myelofibrosis

Primary myelofibrosis (PMF) is a fatal neoplastic disease characterized by clonal myeloproliferation and progressive bone marrow (BM) fibrosis thought to be induced by mesenchymal stromal cells stimulated by overproduced growth factors. However, tissue fibrosis in other diseases is associated with m...

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Published in:The Journal of experimental medicine 2016-08, Vol.213 (9), p.1723-1740
Main Authors: Verstovsek, Srdan, Manshouri, Taghi, Pilling, Darrell, Bueso-Ramos, Carlos E, Newberry, Kate J, Prijic, Sanja, Knez, Liza, Bozinovic, Ksenija, Harris, David M, Spaeth, Erika L, Post, Sean M, Multani, Asha S, Rampal, Raajit K, Ahn, Jihae, Levine, Ross L, Creighton, Chad J, Kantarjian, Hagop M, Estrov, Zeev
Format: Article
Language:English
Subjects:
Animals
Bone Marrow - pathology
Bone Marrow Transplantation
Cells, Cultured
Fibroblasts - drug effects
Fibroblasts - physiology
Fibrosis
Homeodomain Proteins - pharmacology
Humans
Mice
Mice, SCID
Monocytes - cytology
Primary Myelofibrosis - etiology
Primary Myelofibrosis - pathology
Pyrazoles - pharmacology
Recombinant Proteins - pharmacology
Serum Amyloid P-Component - pharmacology
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Summary:Primary myelofibrosis (PMF) is a fatal neoplastic disease characterized by clonal myeloproliferation and progressive bone marrow (BM) fibrosis thought to be induced by mesenchymal stromal cells stimulated by overproduced growth factors. However, tissue fibrosis in other diseases is associated with monocyte-derived fibrocytes. Therefore, we sought to determine whether fibrocytes play a role in the induction of BM fibrosis in PMF. In this study, we show that BM from patients with PMF harbors an abundance of clonal, neoplastic collagen- and fibronectin-producing fibrocytes. Immunodeficient mice transplanted with myelofibrosis patients' BM cells developed a lethal myelofibrosis-like phenotype. Treatment of the xenograft mice with the fibrocyte inhibitor serum amyloid P (SAP; pentraxin-2) significantly prolonged survival and slowed the development of BM fibrosis. Collectively, our data suggest that neoplastic fibrocytes contribute to the induction of BM fibrosis in PMF, and inhibiting fibrocyte differentiation with SAP may interfere with this process.
ISSN:0022-1007
1540-9538
DOI:10.1084/jem.20160283