Neoplastic fibrocytes play an essential role in bone marrow fibrosis in Jak2V617F-induced primary myelofibrosis mice

• Published in: Leukemia Vol. 35; no. 2; pp. 454 - 467
• Main Authors: Ozono, Yoshinori, Shide, Kotaro, Kameda, Takuro, Kamiunten, Ayako, Tahira, Yuki, Sekine, Masaaki, Akizuki, Keiichi, Nakamura, Kenichi, Iwakiri, Hisayoshi, Sueta, Mitsue, Hidaka, Tomonori, Kubuki, Yoko, Yamamoto, Shojiro, Hasuike, Satoru, Sawaguchi, Akira, Nagata, Kenji, Shimoda, Kazuya
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2021; Nature Publishing Group
• Subjects: 13/1; 13/21; 13/31; 13/51; 14/63; 631/250/1904; 631/67/70; 64/60; Anemia; Animals; Bone marrow; Cancer Research; Care and treatment; Cell Differentiation; Cell Proliferation; Collagen; Complications and side effects; Critical Care Medicine; Cytokines; Depletion; Diseases; Fibroblasts - metabolism; Fibroblasts - pathology; Fibronectin; Fibrosis; Growth factors; Health aspects; Hematology; Intensive; Internal Medicine; Janus Kinase 2 - genetics; Janus Kinase 2 - metabolism; Medicine; Medicine & Public Health; Megakaryocytes; Megakaryocytes - metabolism; Megakaryocytes - pathology; Mesenchyme; Mice; Mice, Transgenic; Monocytes; Mutation; Myelofibrosis; Myeloproliferation; Neoplasia; Oncology; Peripheral blood; Primary Myelofibrosis - genetics; Primary Myelofibrosis - metabolism; Primary Myelofibrosis - pathology; Spleen; Splenomegaly; Stem cell transplantation; Stem cells; Stromal cells; Transforming Growth Factor beta1 - genetics; Transforming Growth Factor beta1 - metabolism; Transforming growth factor-b1; Transforming growth factors; Transgenic mice; Japan
• ISSN: 0887-6924; 1476-5551; 1476-5551
• DOI: 10.1038/s41375-020-0880-3

Primary myelofibrosis (PMF) is a myeloproliferative neoplasm (MPN) characterized by clonal myeloproliferation, progressive bone marrow (BM) fibrosis, splenomegaly, and anemia. BM fibrosis was previously thought to be a reactive phenomenon induced by mesenchymal stromal cells that are stimulated by the overproduction of cytokines such as transforming growth factor (TGF)-β1. However, the involvement of neoplastic fibrocytes in BM fibrosis was recently reported. In this study, we showed that the vast majority of collagen- and fibronectin-producing cells in the BM and spleens of Jak2V617F-induced myelofibrosis (MF) mice were fibrocytes derived from neoplastic hematopoietic cells. Neoplastic monocyte depletion eliminated collagen- and fibronectin-producing fibrocytes in BM and spleen, and ameliorated most characteristic MF features in Jak2V617F transgenic mice, including BM fibrosis, anemia, and splenomegaly, while had little effect on the elevated numbers of megakaryocytes and stem cells in BM, and leukothrombocytosis in peripheral blood. TGF-β1, which was produced by hematopoietic cells including fibrocytes, promoted the differentiation of neoplastic monocytes to fibrocytes, and elevated plasma TGF-β1 levels were normalized by monocyte depletion. Collectively, our data suggest that neoplastic fibrocytes are the major contributor to BM fibrosis in PMF, and TGF-β1 is required for their differentiation.