Myeloproliferative leukemia protein activation directly induces fibrocyte differentiation to cause myelofibrosis

Myeloproliferative leukemia protein activation directly induces fibrocyte differentiation to cause myelofibrosis


Play all audios:

Loading...

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


subscription content, access via your institution ACCESS OPTIONS Access through your institution Subscribe to this journal Receive 12 print issues and online access $259.00 per year only


$21.58 per issue Learn more Buy this article * Purchase on SpringerLink * Instant access to full article PDF Buy now Prices may be subject to local taxes which are calculated during checkout


ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS INTERLEUKIN-1 CONTRIBUTES TO


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


Authors * T Maekawa View author publications You can also search for this author inPubMed Google Scholar * Y Osawa View author publications You can also search for this author inPubMed 


Google Scholar * T Izumi View author publications You can also search for this author inPubMed Google Scholar * S Nagao View author publications You can also search for this author inPubMed 


Google Scholar * K Takano View author publications You can also search for this author inPubMed Google Scholar * Y Okada View author publications You can also search for this author inPubMed


 Google Scholar * N Tachi View author publications You can also search for this author inPubMed Google Scholar * M Teramoto View author publications You can also search for this author


inPubMed Google Scholar * T Kawamura View author publications You can also search for this author inPubMed Google Scholar * T Horiuchi View author publications You can also search for this


author inPubMed Google Scholar * R Saga View author publications You can also search for this author inPubMed Google Scholar * S Kato View author publications You can also search for this


author inPubMed Google Scholar * T Yamamura View author publications You can also search for this author inPubMed Google Scholar * J Watanabe View author publications You can also search for


this author inPubMed Google Scholar * A Kobayashi View author publications You can also search for this author inPubMed Google Scholar * S Kobayashi View author publications You can also


search for this author inPubMed Google Scholar * K Sato View author publications You can also search for this author inPubMed Google Scholar * M Hashimoto View author publications You can


also search for this author inPubMed Google Scholar * S Suzu View author publications You can also search for this author inPubMed Google Scholar * F Kimura View author publications You can


also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to T Maekawa. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no conflict of interest.


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


with will be able to read this content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt


content-sharing initiative