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 SLAMF7high MPLhigh monocytes 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. Access through your institution Buy or subscribe This is a preview of

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CLONAL EXPANSION AND PROGRESSION OF BONE MARROW FIBROSIS IN JAK2V617F-INDUCED MYELOPROLIFERATIVE NEOPLASM Article Open access 13 September 2022 INHIBITION OF PROINFLAMMATORY SIGNALING

IMPAIRS FIBROSIS OF BONE MARROW MESENCHYMAL STROMAL CELLS IN MYELOPROLIFERATIVE NEOPLASMS Article Open access 14 March 2022 INHIBITION OF ERK1/2 SIGNALING PREVENTS BONE MARROW FIBROSIS BY

REDUCING OSTEOPONTIN PLASMA LEVELS IN A MYELOFIBROSIS MOUSE MODEL Article Open access 16 March 2023 CHANGE HISTORY * _ 19 SEPTEMBER 2018 Owing to the insufficient specificity of the

anti-myeloproliferative leukemia protein (MPL) antibody in the original version of this Article, Figure 6 and parts of Figures 2a, 4e, and 5a do not represent the correct information. The

corrected version of Figure 6 is shown below and those of Figures 2a, 4e, and 5a are shown in the supplemental information. _ REFERENCES * Tefferi A, Lasho TL, Finke CM, Knudson RA,

Ketterling R, Hanson CH _et al_. CALR vs JAK2 vs MPL-mutated or triple-negative myelofibrosis: clinical, cytogenetic and molecular comparisons. _Leukemia_ 2014; 28: 1472–1477. Article  CAS 

PubMed  Google Scholar  * Hitchcock IS, Kaushansky K . Thrombopoietin from beginning to end. _Br J Haematol_ 2014; 165: 259–268. Article  CAS  PubMed  Google Scholar  * Ku H, Yonemura Y,

Kaushansky K, Ogawa M . Thrombopoietin, the ligand for the Mpl receptor, synergizes with steel factor and other early acting cytokines in supporting proliferation of primitive hematopoietic

progenitors of mice. _Blood_ 1996; 87: 4544–4551. CAS  PubMed  Google Scholar  * Yan XQ, Lacey D, Fletcher F, Hartley C, McElroy P, Sun Y _et al_. Chronic exposure to retroviral vector

encoded MGDF (mpl-ligand) induces lineage-specific growth and differentiation of megakaryocytes in mice. _Blood_ 1995; 86: 4025–4033. CAS  PubMed  Google Scholar  * Villeval JL, Cohen-Solal

K, Tulliez M, Giraudier S, Guichard J, Burstein SA _et al_. High thrombopoietin production by hematopoietic cells induces a fatal myeloproliferative syndrome in mice. _Blood_ 1997; 90:

4369–4383. CAS  PubMed  Google Scholar  * Pikman Y, Lee BH, Mercher T, McDowell E, Ebert BL, Gozo M _et al_. MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid

metaplasia. _PLoS Med_ 2006; 3: e270. Article  PubMed Central  PubMed  Google Scholar  * Kuter DJ, Mufti GJ, Bain BJ, Hasserjian RP, Davis W, Rutstein M . Evaluation of bone marrow reticulin

formation in chronic immune thrombocytopenia patients treated with romiplostim. _Blood_ 2009; 114: 3748–3756. Article  CAS  PubMed  Google Scholar  * Chagraoui H, Komura E, Tulliez M,

Giraudier S, Vainchenker W, Wendling F . Prominent role of TGF-beta 1 in thrombopoietin-induced myelofibrosis in mice. _Blood_ 2002; 100: 3495–3503. Article  CAS  PubMed  Google Scholar  *

Ciurea SO, Merchant D, Mahmud N, Ishii T, Zhao Y, Hu W _et al_. Pivotal contributions of megakaryocytes to the biology of idiopathic myelofibrosis. _Blood_ 2007; 110: 986–993. Article  CAS 

PubMed Central  PubMed  Google Scholar  * Pilling D, Buckley CD, Salmon M, Gomer RH . Inhibition of fibrocyte differentiation by serum amyloid P. _J Immunol_ 2003; 171: 5537–5546. Article 

CAS  PubMed  Google Scholar  * Verstovsek S, Manshouri T, Pilling D, Bueso-Ramos CE, Newberry KJ, Prijic S _et al_. Role of neoplastic monocyte-derived fibrocytes in primary myelofibrosis.

_J Exp Med_ 2016; 213: 1723–1740. Article  CAS  PubMed Central  PubMed  Google Scholar  * Bucala R, Spiegel LA, Chesney J, Hogan M, Cerami A . Circulating fibrocytes define a new leukocyte

subpopulation that mediates tissue repair. _Mol Med_ 1994; 1: 71–81. Article  CAS  PubMed Central  PubMed  Google Scholar  * Abe R, Donnelly SC, Peng T, Bucala R, Metz CN . Peripheral blood

fibrocytes: differentiation pathway and migration to wound sites. _J Immunol_ 2001; 166: 7556–7562. Article  CAS  PubMed  Google Scholar  * Pilling D, Fan T, Huang D, Kaul B, Gomer RH .

Identification of markers that distinguish monocyte-derived fibrocytes from monocytes, macrophages, and fibroblasts. _PLoS ONE_ 2009; 4: e7475. Article  PubMed Central  PubMed  Google

Scholar  * Mehrad B, Strieter RM . Fibrocytes and the pathogenesis of diffuse parenchymal lung disease. _Fibrogenesis Tissue Repair_ 2012; 5: S22. Article  PubMed Central  PubMed  Google

Scholar  * Keeley EC, Mehrad B, Strieter RM . The role of fibrocytes in fibrotic diseases of the lungs and heart. _Fibrogenesis Tissue Repair_ 2011; 4: 2. Article  PubMed Central  PubMed 

Google Scholar  * Kisseleva T, Uchinami H, Feirt N, Quintana-Bustamante O, Segovia JC, Schwabe RF _et al_. Bone marrow-derived fibrocytes participate in pathogenesis of liver fibrosis. _J

Hepatol_ 2006; 45: 429–438. Article  CAS  PubMed  Google Scholar  * Reich B, Schmidbauer K, Rodriguez Gomez M, Johannes Hermann F, Gobel N, Bruhl H _et al_. Fibrocytes develop outside the

kidney but contribute to renal fibrosis in a mouse model. _Kidney Int_ 2013; 84: 78–89. Article  CAS  PubMed  Google Scholar  * Reilkoff RA, Bucala R, Herzog EL . Fibrocytes: emerging

effector cells in chronic inflammation. _Nat Rev Immunol_ 2011; 11: 427–435. Article  CAS  PubMed Central  PubMed  Google Scholar  * Yanai N, Suzuki M, Obinata M . Hepatocyte cell lines

established from transgenic mice harboring temperature-sensitive simian virus 40 large T-antigen gene. _Exp Cell Res_ 1991; 197: 50–56. Article  CAS  PubMed  Google Scholar  * Obinata M .

Conditionally immortalized cell lines with differentiated functions established from temperature-sensitive T-antigen transgenic mice. _Genes Cells_ 1997; 2: 235–244. Article  CAS  PubMed 

Google Scholar  * Crawford JR, Pilling D, Gomer RH . Improved serum-free culture conditions for spleen-derived murine fibrocytes. _J Immunol Methods_ 2010; 363: 9–20. Article  CAS  PubMed

Central  PubMed  Google Scholar  * Pilling D, Vakil V, Gomer RH . Improved serum-free culture conditions for the differentiation of human and murine fibrocytes. _J Immunol Methods_ 2009;

351: 62–70. Article  CAS  PubMed Central  PubMed  Google Scholar  * Thiele J, Kvasnicka HM, Facchetti F, Franco V, van der Walt J, Orazi A . European consensus on grading bone marrow

fibrosis and assessment of cellularity. _Haematologica_ 2005; 90: 1128–1132. PubMed  Google Scholar  * Quintas-Cardama A, Vaddi K, Liu P, Manshouri T, Li J, Scherle PA _et al_. Preclinical

characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms. _Blood_ 2010; 115: 3109–3117. Article  CAS  PubMed

Central  PubMed  Google Scholar  * Sangkhae V, Etheridge SL, Kaushansky K, Hitchcock IS . The thrombopoietin receptor, MPL, is critical for development of a JAK2V617F-induced

myeloproliferative neoplasm. _Blood_ 2014; 124: 3956–3963. Article  CAS  PubMed Central  PubMed  Google Scholar  * Wang X, Haylock D, Hu CS, Kowalczyk W, Jiang T, Qiu J _et al_. A

thrombopoietin receptor antagonist is capable of depleting myelofibrosis hematopoietic stem and progenitor cells. _Blood_ 2016; 127: 3398–3409. Article  CAS  PubMed Central  PubMed  Google

Scholar  * Ramos P, Casu C, Gardenghi S, Breda L, Crielaard BJ, Guy E _et al_. Macrophages support pathological erythropoiesis in polycythemia vera and beta-thalassemia. _Nat Med_ 2013; 19:

437–445. Article  CAS  PubMed Central  PubMed  Google Scholar  * Hashimoto M, Nasser H, Bhuyan F, Kuse N, Satou Y, Harada S _et al_. Fibrocytes differ from macrophages but can be infected

with HIV-1. _J Immunol_ 2015; 195: 4341–4350. Article  CAS  PubMed  Google Scholar  * Zahr AA, Salama ME, Carreau N, Tremblay D, Verstovsek S, Mesa R _et al_. Bone marrow fibrosis in

myelofibrosis: pathogenesis, prognosis and targeted strategies. _Haematologica_ 2016; 101: 660–671. Article  PubMed Central  PubMed  Google Scholar  * Mascarenhas J, Li T, Sandy L, Newsom C,

Petersen B, Godbold J _et al_. Anti-transforming growth factor-beta therapy in patients with myelofibrosis. _Leuk Lymphoma_ 2014; 55: 450–452. Article  PubMed  Google Scholar  * Mesa RA,

Tefferi A, Elliott MA, Hoagland HC, Call TG, Schroeder GS _et al_. A phase II trial of pirfenidone (5-methyl-1-phenyl-2-[1H]-pyridone), a novel anti-fibrosing agent, in myelofibrosis with

myeloid metaplasia. _Br J Haematol_ 2001; 114: 111–113. Article  CAS  PubMed  Google Scholar  * Crawford JR, Pilling D, Gomer RH . FcgammaRI mediates serum amyloid P inhibition of fibrocyte

differentiation. _J Leukoc Biol_ 2012; 92: 699–711. Article  CAS  PubMed Central  PubMed  Google Scholar  * Duffield JS, Lupher ML Jr . PRM-151 (recombinant human serum amyloid P/pentraxin

2) for the treatment of fibrosis. _Drug News Perspect_ 2010; 23: 305–315. Article  CAS  PubMed  Google Scholar  * Veillette A, Guo H . CS1, a SLAM family receptor involved in immune

regulation, is a therapeutic target in multiple myeloma. _Crit Rev Oncol Hematol_ 2013; 88: 168–177. Article  PubMed  Google Scholar  * Jakubowiak A, Offidani M, Pegourie B, De La Rubia J,

Garderet L, Laribi K _et al_. Randomized phase 2 study: elotuzumab plus bortezomib/dexamethasone vs bortezomib/dexamethasone for relapsed/refractory MM. _Blood_ 2016; 127: 2833–2840. Article

  CAS  PubMed Central  PubMed  Google Scholar  * Wang JC, Chen C, Lou LH, Mora M . Blood thrombopoietin, IL-6 and IL-11 levels in patients with agnogenic myeloid metaplasia. _Leukemia_ 1997;

11: 1827–1832. Article  CAS  PubMed  Google Scholar  * Cerutti A, Custodi P, Duranti M, Noris P, Balduini CL . Thrombopoietin levels in patients with primary and reactive thrombocytosis.

_Br J Haematol_ 1997; 99: 281–284. Article  CAS  PubMed  Google Scholar  Download references AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Division of Hematology, Department of Internal

Medicine, National Defense Medical College, Tokorozawa, Japan T Maekawa, Y Osawa, T Izumi, S Nagao, K Takano, Y Okada, N Tachi, M Teramoto, T Kawamura, T Horiuchi, R Saga, S Kato, T

Yamamura, J Watanabe, A Kobayashi, S Kobayashi, K Sato & F Kimura * Suzu Project Laboratory, Center for AIDS Research, Kumamoto University, Kumamoto, Japan M Hashimoto & S Suzu

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RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Maekawa, T., Osawa, Y., Izumi, T. _et al._ Myeloproliferative leukemia protein activation directly

induces fibrocyte differentiation to cause myelofibrosis. _Leukemia_ 31, 2709–2716 (2017). https://doi.org/10.1038/leu.2017.112 Download citation * Received: 18 November 2016 * Revised: 22

March 2017 * Accepted: 28 March 2017 * Published: 03 April 2017 * Issue Date: December 2017 * DOI: https://doi.org/10.1038/leu.2017.112 SHARE THIS ARTICLE Anyone you share the following link

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