title: Myeloproliferative leukemia protein activation directly induces fibrocyte differentiation to cause myelofibrosis.
abstract: Myelofibrosis (MF) may be caused by various pathogenic mechanisms such as elevation in circulating cytokine levels, cellular interactions and genetic mutations. However, the underlying mechanism of MF still remains unknown. Recent studies have revealed that fibrocytes, the spindle-shaped fibroblast-like hematopoietic cells, and the thrombopoietin (TPO)/myeloproliferative leukemia protein (MPL; TPO receptor) signaling pathway play a certain role in the development of MF. In the present study, we aimed to investigate the relationship between fibrocytes and MPL activation. We showed that TPO or a TPO receptor agonist directly induces fibrocyte differentiation using murine fibrocyte cell lines and a murine MF model. Conversely, elimination of macrophages expressing MPL by clodronate liposomes reversed the MF phenotype of the murine model, suggesting that fibrocyte differentiation induced by MPL activation contributes to the progression of MF. Furthermore, we revealed that SLAMF7highMPLhighmonocytes in human peripheral blood mononuclear cells were possible fibrocyte precursors and that these cells increased in number in MF patients not treated with ruxolitinib. Our findings confirmed a link between fibrocytes and the TPO/MPL signaling pathway, which could result in a greater understanding of the pathogenesis of MF and lead to the development of novel therapeutic interventions.
authors.affiliation: Division of Hematology, Department of Internal Medicine, National Defense Medical College, Tokorozawa, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Maekawa
authors.affiliation: Division of Hematology, Department of Internal Medicine, National Defense Medical College, Tokorozawa, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Osawa
authors.affiliation: Division of Hematology, Department of Internal Medicine, National Defense Medical College, Tokorozawa, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Izumi
authors.affiliation: Division of Hematology, Department of Internal Medicine, National Defense Medical College, Tokorozawa, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Nagao
authors.affiliation: Division of Hematology, Department of Internal Medicine, National Defense Medical College, Tokorozawa, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Takano
authors.affiliation: Division of Hematology, Department of Internal Medicine, National Defense Medical College, Tokorozawa, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Okada
authors.affiliation: Division of Hematology, Department of Internal Medicine, National Defense Medical College, Tokorozawa, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Tachi
authors.affiliation: Division of Hematology, Department of Internal Medicine, National Defense Medical College, Tokorozawa, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Teramoto
authors.affiliation: Division of Hematology, Department of Internal Medicine, National Defense Medical College, Tokorozawa, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kawamura
authors.affiliation: Division of Hematology, Department of Internal Medicine, National Defense Medical College, Tokorozawa, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Horiuchi
authors.affiliation: Division of Hematology, Department of Internal Medicine, National Defense Medical College, Tokorozawa, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Saga
authors.affiliation: Division of Hematology, Department of Internal Medicine, National Defense Medical College, Tokorozawa, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Kato
authors.affiliation: Division of Hematology, Department of Internal Medicine, National Defense Medical College, Tokorozawa, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Yamamura
authors.affiliation: Division of Hematology, Department of Internal Medicine, National Defense Medical College, Tokorozawa, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Watanabe
authors.affiliation: Division of Hematology, Department of Internal Medicine, National Defense Medical College, Tokorozawa, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Kobayashi
authors.affiliation: Division of Hematology, Department of Internal Medicine, National Defense Medical College, Tokorozawa, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Kobayashi
authors.affiliation: Division of Hematology, Department of Internal Medicine, National Defense Medical College, Tokorozawa, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Sato
authors.affiliation: Suzu Project Laboratory, Center for AIDS Research, Kumamoto University, Kumamoto, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Hashimoto
authors.affiliation: Suzu Project Laboratory, Center for AIDS Research, Kumamoto University, Kumamoto, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Suzu
authors.affiliation: Division of Hematology, Department of Internal Medicine, National Defense Medical College, Tokorozawa, Japan.
authors.forename: F
authors.initials: F
authors.lastname: Kimura
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D002460:Cell Line; D004002:Clodronic Acid / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D053614:Janus Kinase 2 / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D010641:Phenotype; D055728:Primary Myelofibrosis / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D053628:Receptors, Thrombopoietin / Q000378:metabolism*; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction; D013926:Thrombopoietin / Q000378:metabolism
chemical_list: D053628:Receptors, Thrombopoietin; D050791:STAT Transcription Factors; D004002:Clodronic Acid; C082218:MPL protein, human; D013926:Thrombopoietin; D053614:Janus Kinase 2