Skip to main content

Advertisement

SpringerLink
Log in

An Immune Dysregulation in MPN

  • Myeloproliferative Disorders (C Harrison, Section Editor)
  • Published:
Current Hematologic Malignancy Reports Aims and scope Submit manuscript

Abstract

Myeloproliferative neoplasms (MPNs) are stem cell-derived clonal myeloid malignancies characterized by a unique somatic mutational profile since three mutually exclusive mutations (JAK2V617F, MPL, and CALR) sustain the great majority of the cases. However, clinical observation that autoimmune diseases may predispose to MPNs, autoimmune disorders or autoimmune phenomena may be associated with MPNs, and genetic constitutional variants that predispose to autoimmune disorders or inflammatory phenomena also predispose to MPNs raises a hypothesis that there might be an autoimmune/inflammatory basis underlying the pathogenesis of MPNs. Recent studies have documented that MPNs are characterized by an abnormal activity of key cells of the immune system, for example, increase in monocyte/macrophage compartment, altered regulatory T cell frequency, expansion of myeloid-derived suppressor cells, and CD4/natural killer cell dysfunction. This review is focused on summarizing recent advances in our understanding of immunological defects in MPNs with accompanying translational implications.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as • Of importance •• Of major importance

  1. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74.

    Article  CAS  PubMed  Google Scholar 

  2. Landskron G, De la Fuente M, Thuwajit P, Thuwajit C, Hermoso MA. Chronic inflammation and cytokines in the tumor microenvironment. J Immunol Res. 2014;2014:149185.

    Article  PubMed Central  PubMed  Google Scholar 

  3. Rachidi SM, Qin T, Sun S, Zheng WJ, Li Z. Molecular profiling of multiple human cancers defines an inflammatory cancer-associated molecular pattern and uncovers KPNA2 as a uniform poor prognostic cancer marker. PLoS One. 2013;8(3):e57911.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Hasselblach H. Idiopathic myelofibrosis: a clinical study of 80 patients. Am J Hematol. 1990;34(4):291–300.

    Article  Google Scholar 

  5. Vainchenker W, Constantinescu SN. JAK/STAT signaling in haematological malignancies. Oncogene. 2013;32(21):2601–13.

    Article  CAS  PubMed  Google Scholar 

  6. Squires M, Harrison CN, Barosi G, et al. The relationship between cytokine levels and symptoms in patients (pts) with myelofibrosis (MF) from COMFORT-II, a phase 3 study of ruxolitinib (RUX) vs best available therapy (BAT). Blood. 2013; 122(2), Abstract 2070

  7. Cervantes F, Vannucchi AM, Kiladjian JJ, et al. Three-year efficacy, safety, and survival findings from COMFORT-II, a phase 3 study comparing ruxolitinib with best available therapy for myelofibrosis. Blood. 2013;122(25):4047–53. This is an updated analysis of the results obtained with ruxolitinib in myelofibrosis patients after a 3-year follow-up. The results indicate that the drug, an anti-cytokine agent, is able to prolong the survival of patients.

    Article  CAS  PubMed  Google Scholar 

  8. Anderson LA, Pfeiffer RM, Landgren O, Gadalla S, Berndt SI, Engels EA. Risks of myeloid malignancies in patients with autoimmune conditions. Br J Cancer. 2009;100(5):822–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Kristinsson SY, Landgren O, Samuelsson J, Björkholm M, Goldin LR. Autoimmunity and the risk of myeloproliferative neoplasms. Haematologica. 2010;95(7):1216–20.

    Article  PubMed Central  PubMed  Google Scholar 

  10. Hemminki K, Liu X, Försti A, Ji J, Sundquist J, Sundquist K. Subsequent leukaemia in autoimmune disease patients. Br J Haematol. 2013;161(5):677–87.

    Article  CAS  PubMed  Google Scholar 

  11. Guillot X, Moldovan M, Vidon C, Wendling D. Myelofibrosis-related arthritis successfully treated with hydroxyurea. Case Rep Rheumatol. 2014;2014:869743.

    PubMed Central  PubMed  Google Scholar 

  12. Thorsteinsdottir S, Bjerrum OW, Hasselbalch HC. Myeloproliferative neoplasms in five multiple sclerosis patients. Leuk Res Rep. 2013;2(2):61–3.

    PubMed Central  PubMed  Google Scholar 

  13. Ayvaz OC, Yavasoglu I, Kadikoylu G, Bozkurt G, Bolaman Z. Thrombocytosis in rheumatoid arthritis: JAK2V617F-positive essential thrombocythemia. Rheumatol Int. 2012;32(1):269–71.

    Article  CAS  PubMed  Google Scholar 

  14. Fischer M, Helper DJ, Chiorean MV. Myeloproliferative disorders in patients with inflammatory bowel disease on anti-TNF-α therapy: report of two cases and review of the literature. Inflamm Bowel Dis. 2011;17(2):674–5.

    Article  PubMed  Google Scholar 

  15. Ong A, Quach H, Leech M. Reversal of transfusion dependence by tumor necrosis factor inhibitor treatment in a patient with concurrent rheumatoid arthritis and primary myelofibrosis. J Clin Rheumatol. 2011;17(4):211–3.

    Article  PubMed  Google Scholar 

  16. Muslimani A, Ahluwalia MS, Palaparty P, Daw HA. Idiopathic myelofibrosis associated with dermatomyositis. Am J Hematol. 2006;81(7):559–60.

    Article  PubMed  Google Scholar 

  17. Ito A, Umeda M, Koike T, Naruse S, Fujita N. A case of dermatomyositis associated with chronic idiopathic myelofibrosis. Rinsho Shinkeigaku. 2006;46(3):210–3.

    PubMed  Google Scholar 

  18. Jain V, Maheshwari A, Gulati S, Kabra M, Kalra V. Juvenile rheumatoid arthritis with myelofibrosis with myeloid metaplasia. Indian J Pediatr. 2005;72(9):789–91.

    Article  PubMed  Google Scholar 

  19. Camós M, Arellano-Rodrigo E, Abelló D, et al. Idiopathic myelofibrosis associated with classic polyarteritis nodosa. Leuk Lymphoma. 2003;44(3):539–41.

    Article  PubMed  Google Scholar 

  20. Arellano-Rodrigo E, Esteve J, Giné E, Panés J, Cervantes F. Idiopathic myelofibrosis associated with ulcerative colitis. Leuk Lymphoma. 2002;43(7):1481–3.

    Article  PubMed  Google Scholar 

  21. Hernández-Boluda JC, Jiménez M, Rosiñol L, Cervantes F. Idiopathic myelofibrosis associated with primary biliary cirrhosis. Leuk Lymphoma. 2002;43(3):673–4.

    Article  PubMed  Google Scholar 

  22. Tsiara SN, Christou L, Panteli K, Anastasopoulos D, Bourantas KL. A patient with essential thrombocytosis and multiple sclerosis. Eur J Intern Med. 2000;11(6):345–7.

    Article  PubMed  Google Scholar 

  23. Ros Expósito S, Rodríguez Moreno J, Campoy Reolid E, Roig Escofet D. Idiopathic myelofibrosis associated with rheumatoid arthritis. Med Clin (Barc). 1994;102(7):277.

    Google Scholar 

  24. Rondeau E, Solal-Celigny P, Dhermy D, et al. Immune disorders in agnogenic myeloid metaplasia: relations to myelofibrosis. Br J Haematol. 1983;53(3):467–75.

    Article  CAS  PubMed  Google Scholar 

  25. Lang JM, Oberling F, Giron C, Mayer S. Autoimmunité et deficit de immunité cellulaire au cours des fibroses primitives de la moelle osseuse. Ann Immunol Paris. 1977;128(1–2):291–3.

    CAS  PubMed  Google Scholar 

  26. Caligaris Cappio F, Vigliani R, Novarino A, et al. Idiopathic myelofibrosis: a possible role for immune-complexes in the pathogenesis of bone marrow fibrosis. Br J Haematol. 1981;49(1):17–21.

    Article  Google Scholar 

  27. Khumbanonda M, Horowitz HI, Eysker ME. Coomb’s positive hemolytic anemia in myelofibrosis with myeloid metaplasia. Am J Med Sci. 1969;258(2):89–93.

    Article  CAS  PubMed  Google Scholar 

  28. Barcellini W, Iurlo A, Radice T, et al. Increased prevalence of autoimmune phenomena in myelofibrosis: relationship with clinical and morphological characteristics, and with immunoregulatory cytokine patterns. Leuk Res. 2013;37(11):1509–15. The paper reports the results of autoimmune tests in 100 patients with MF, and document that 45% of the patients had positive anti-erythrocyte antibodies by mitogen-stimulated direct antiglobulin test, a functional assay able to disclose a latent autoimmunity.

    Article  CAS  PubMed  Google Scholar 

  29. Bernhardt B, Valletta M. Lupus anticoagulant in myelofibrosis. Am J Med Sci. 1976;272(2):229–31.

    Article  CAS  PubMed  Google Scholar 

  30. Hasselbalch H, Berild D, Paaske-Hansen O. Platelet-associated IgG and IgM in myelofibrosis. Scand J Haematol. 1984;32(5):488–92.

    Article  CAS  PubMed  Google Scholar 

  31. Gordon BR, Coleman M, Kohen P, Day NK. Immunological abnormalities in myelofibrosis with activation of the complement system. Blood. 1981;58(5):904–10.

    CAS  PubMed  Google Scholar 

  32. Lewis CM, Pegrum GD. Immune complexes in myelofibrosis: a possible guide to management. Br J Haematol. 1978;39(2):233–9.

    Article  CAS  PubMed  Google Scholar 

  33. Paquette RL, Meshkinpour A, Rosen PJ. Autoimmune myelofibrosis. A steroid-responsive cause of bone marrow fibrosis associated with systemic lupus erythematosus. Med (Baltimore). 1994;73(3):145–52.

    Article  CAS  Google Scholar 

  34. Pullarkat V, Bass RD, Gong JZ, Feinstein DI, Brynes RK. Primary autoimmune myelofibrosis: definition of a distinct clinicopathologic syndrome. Am J Hematol. 2003;72(1):8–12.

    Article  PubMed  Google Scholar 

  35. Pillai A, Gautam M, Williamson H, Martlew V, Nash J, Thachil J. Multisystem failure due to three coexisting autoimmune diseases. Intern Med. 2009;48(10):837–42.

    Article  PubMed  Google Scholar 

  36. Bass RD, Pullarkat V, Feinstein DI, Kaul A, Winberg CD, Brynes RK. Pathology of autoimmune myelofibrosis. A report of three cases and a review of the literature. Am J Clin Pathol. 2001;116(2):211–6.

    Article  CAS  PubMed  Google Scholar 

  37. Jain P, Lin P, Bueso-Ramos C, Verstovsek S, Pemmaraju N. Primary autoimmune myelofibrosis (MF) with high-grade peripheral T-cell lymphoma (PTCL) NOS. Eur J Haematol. 2013;91(4):378–9.

    PubMed  Google Scholar 

  38. Sacré K, Aguilar C, Deligny C, et al. Lytic bone lesions in lupus-associated myelofibrosis. Lupus. 2010;19(3):313–6.

    Article  PubMed  Google Scholar 

  39. Pereira RM, Velloso ER, Menezes Y, Gualandro S, Vassalo J, Yoshinari NH. Bone marrow findings in systemic lupus erythematosus patients with peripheral cytopenias. Clin Rheumatol. 1998;17(3):219–22.

    Article  CAS  PubMed  Google Scholar 

  40. Wanitpongpun C, Teawtrakul N, Mahakkanukrauh A, Siritunyaporn S, Sirijerachai C, Chansung K. Bone marrow abnormalities in systemic lupus erythematosus with peripheral cytopenia. Clin Exp Rheumatol. 2012;30(6):825–9.

    PubMed  Google Scholar 

  41. Takahashi T. Autoimmune myelofibrosis accompanied by Sjögren’s syndrome in a 47, XXX/46, XX mosaic woman. Intern Med. 2014;53(7):783–7.

    Article  PubMed  Google Scholar 

  42. Jones AV, Chase A, Silver RT, et al. JAK2 haplotype is a major risk factor for the development of myeloproliferative neoplasms. Nat Genet. 2009;41(4):446–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Olcaydu D, Harutyunyan A, Jäger R, et al. A common JAK2 haplotype confers susceptibility to myeloproliferative neoplasms. Nat Genet. 2009;41(4):450–4.

    Article  CAS  PubMed  Google Scholar 

  44. Jones AV, Campbell PJ, Beer PA, et al. The JAK2 46/1 haplotype predisposes to MPL-mutated myeloproliferative neoplasms. Blood. 2010;115(22):4517–23.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  45. Barrett JC, Hansoul S, Nicolae DL, et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn’s disease. Nat Genet. 2008;40(8):955–62.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  46. Ferguson LR, Han DY, Fraser AG, et al. Genetic factors in chronic inflammation: single nucleotide polymorphisms in the STAT-JAK pathway, susceptibility to DNA damage and Crohn’s disease in a New Zealand population. Mutat Res. 2010;690(1–2):108–15.

    Article  CAS  PubMed  Google Scholar 

  47. Hermouet S, Vilaine M. The JAK2 46/1 haplotype: a marker of inappropriate myelomonocytic response to cytokine stimulation, leading to increased risk of inflammation, myeloid neoplasm, and impaired defense against infection? Haematologica. 2011;96(11):1575–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  48. Varricchio L, Godbold J, Scott SA, et al. Increased frequency of the glucocorticoid receptor A3669G (rs6198) polymorphism in patients with Diamond-Blackfan anemia. Blood. 2011;118(2):473–4.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  49. Poletto V, Rosti V, Villani L, et al. A3669G polymorphism of glucocorticoid receptor is a susceptibility allele for primary myelofibrosis and contributes to phenotypic diversity and blast transformation. Blood. 2012;120(15):3112–7. The paper documents that the polymorphism A3669G of the glucocorticoid receptor is a susceptibility factor for myelofibrosis. Since the polymorphism is also a predisposing factor for rheumatoid arthritis, it represents a proof of concept of common genetic predisposition to MPNs and inflammatory disorders.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  50. Derijk RH, Schaaf MJ, Turner G, et al. A human glucocorticoid receptor gene variant that increases the stability of the glucocorticoid receptor beta-isoform mRNA is associated with rheumatoid arthritis. J Rheumatol. 2001;28(11):2383–8.

    CAS  PubMed  Google Scholar 

  51. Varricchio L, Masselli E, Alfani E, et al. The dominant negative β isoform of the glucocorticoid receptor is uniquely expressed in erythroid cells expanded from polycythemia vera patients. Blood. 2011;118(2):425–36.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  52. van Oosten MJ, Dolhain RJ, Koper JW, et al. Polymorphisms in the glucocorticoid receptor gene that modulate glucocorticoid sensitivity are associated with rheumatoid arthritis. Arthritis Res Ther. 2010;12(4):R159.

    Article  PubMed Central  PubMed  Google Scholar 

  53. Oddsson A, Kristinsson SY, Helgason H, et al. The germline sequence variant rs2736100_C in TERT associates with myeloproliferative neoplasms. Leukemia. 2014;28(6):1371–4.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  54. Wang F, Fu P, Pang Y, et al. TERT rs2736100T/G polymorphism upregulates interleukin 6 expression in non-small cell lung cancer especially in adenocarcinoma. Tumour Biol. 2014;35(5):4667–72.

    Article  CAS  PubMed  Google Scholar 

  55. Skov V, Larsen TS, Thomassen M, et al. Molecular profiling of peripheral blood cells from patients with polycythemia vera and related neoplasms: identification of deregulated genes of significance for inflammation and immune surveillance. Leuk Res. 2012;36(11):1387–92.

    Article  CAS  PubMed  Google Scholar 

  56. Skov V, Riley CH, Thomassen M, et al. Whole blood transcriptional profiling reveals significant down-regulation of human leukocyte antigen class I and II genes in essential thrombocythemia, polycythemia vera and myelofibrosis. Leuk Lymphoma. 2013;54(10):2269–73.

    Article  CAS  PubMed  Google Scholar 

  57. Skov V, Larsen TS, Thomassen M, et al. Whole-blood transcriptional profiling of interferon-inducible genes identifies highly upregulated IFI27 in primary myelofibrosis. Eur J Haematol. 2011;87(1):54–60.

    Article  CAS  PubMed  Google Scholar 

  58. Kremer M, Horn T, Koch I, et al. Quantitation of the JAK2V617F mutation in microdissected bone marrow trephines: equal mutational load in myeloid lineages and rare involvement of lymphoid cells. Am J Surg Pathol. 2008;32(6):928–35.

    Article  PubMed  Google Scholar 

  59. Pardanani A, Lasho TL, Finke C, et al. Extending Jak2V617F and MplW515 mutation analysis to single hematopoietic colonies and B and T lymphocytes. Stem Cells. 2007;25(9):2358–62.

    Article  CAS  PubMed  Google Scholar 

  60. Pardanani A, Lasho TL, Finke C, Markovic SN, Tefferi A. Demonstration of MPLW515K, but not JAK2V617F, in in vitro expanded CD4+ T lymphocytes. Leukemia. 2007;21(10):2206–7.

    Article  CAS  PubMed  Google Scholar 

  61. Larsen TS, Christensen JH, Hasselbalch HC, Pallisgaard N. The JAK2 V617F mutation involves B- and T-lymphocyte lineages in a subgroup of patients with Philadelphia-chromosome negative chronic myeloproliferative disorders. Br J Haematol. 2007;136(5):745–51.

    Article  CAS  PubMed  Google Scholar 

  62. Bogani C, Guglielmelli P, Antonioli E, Pancrazzi A, Bosi A, Vannucchi AM. B-, T-, and NK-cell lineage involvement in JAK2V617F-positive patients with idiopathic myelofibrosis. Haematologica. 2007;92(2):258–9.

    Article  PubMed  Google Scholar 

  63. Reeder TL, Bailey RJ, Dewald GW, Tefferi A. Both B and T lymphocytes may be clonally involved in myelofibrosis with myeloid metaplasia. Blood. 2003;101(5):1981–3.

    Article  CAS  PubMed  Google Scholar 

  64. Delhommeau F, Dupont S, Tonetti C, et al. Evidence that the JAK2 G1849T (V617F) mutation occurs in a lymphomyeloid progenitor in polycythemia vera and idiopathic myelofibrosis. Blood. 2007;109(1):71–7.

    Article  CAS  PubMed  Google Scholar 

  65. Cervantes F, Hernández-Boluda JC, Villamor N, Serra A, Montserrat E. Assessment of peripheral blood lymphocyte subsets in idiopathic myelofibrosis. Eur J Haematol. 2000;65(2):104–8.

    Article  CAS  PubMed  Google Scholar 

  66. Ginsberg HN, Le NA, Gilbert HS. Altered high density lipoprotein metabolism in patients with myeloproliferative disorders and hypocholesterolemia. Metabolism. 1986;35(9):878–82.

    Article  CAS  PubMed  Google Scholar 

  67. Ginsberg H, Gilbert HS. Hypocholesterolemia in myeloproliferative diseases with myelofibrosis. Prog Clin Biol Res. 1984;154:345–57.

    CAS  PubMed  Google Scholar 

  68. Ginsberg H, Gilbert HS, Gibson JC, Le NA, Brown WV. Increased low-density-lipoprotein catabolism in myeloproliferative disorders. Ann Intern Med. 1982;96(3):311–6.

    Article  CAS  PubMed  Google Scholar 

  69. Thiele J, Kvasnicka HM, Boeltken B. Resident bone marrow macrophages in idiopathic (primary) myelofibrosis (IMF): a histochemical and morphometric study on sequential trephine biopsies. Leuk Res. 1999;23(11):983–5.

    Article  CAS  PubMed  Google Scholar 

  70. Elliott MA, Verstovsek S, Dingli D, et al. Monocytosis is an adverse prognostic factor for survival in younger patients with primary myelofibrosis. Leuk Res. 2007;31(11):1503–9.

    Article  CAS  PubMed  Google Scholar 

  71. Boiocchi L, Espinal-Witter R, Geyer JT, et al. Development of monocytosis in patients with primary myelofibrosis indicates an accelerated phase of the disease. Mod Pathol. 2013;26(2):204–12.

    Article  CAS  PubMed  Google Scholar 

  72. Noy R, Pollard JW. Tumor-associated macrophages: from mechanisms to therapy. Immunity. 2014;41(1):49–61.

    Article  CAS  PubMed  Google Scholar 

  73. Rameshwar P, Narayanan R, Qian J, et al. NF-kappa B as a central mediator in the induction of TGF-beta in monocytes from patients with idiopathic myelofibrosis: an inflammatory response beyond the realm of homeostasis. J Immunol. 2000;165(4):2271–7.

    Article  CAS  PubMed  Google Scholar 

  74. Chang VT, Yook C, Rameshwar P. Synergism between fibronectin and transforming growth factor-β1 in the production of substance P in monocytes of patients with myelofibrosis. Leuk Lymphoma. 2013;54(3):631–8.

    Article  CAS  PubMed  Google Scholar 

  75. Kundra A, Baptiste S, Chen C, Sindhu H, Wang JJC. Programmed cell death receptor (PD-1), PD-1 ligand (PD-L1) expression and myeloid derived suppressor cells (MDSC) in myeloid neoplasms implicate the mechanism of IMiD treatment of myelofibrosis. Blood. 2013;122(21) Abstract n. 2837

  76. Zhao WB, Li Y, Liu X, Zhang LY, Wang X. Involvement of CD4+CD25+ regulatory T cells in the pathogenesis of polycythaemia vera. Chin Med J (Engl). 2008;121(18):1781–6.

    CAS  Google Scholar 

  77. Keohane C, Kordasti SY, Seidl T et al. JAK inhibition reduces CD25 high CD27+FOXp3+ T regulatory cells and causes a silencing of T effector cells in patients with myeloproliferative neoplasms whilst promoting a TH17 phenotype. Blood 2013;122(21) Abstract n 4092

  78. Riley CH, Jensen MK, Brimnes MK, et al. Increase in circulating CD4+CD25+Foxp3+ T cells in patients with Philadelphia-negative chronic myeloproliferative neoplasms during treatment with IFN-α. Blood. 2011;118(8):2170–3.

    Article  PubMed  Google Scholar 

  79. Pourcelot E, Trocme C, Mondet J, et al. Cytokine profiles in polycythemia vera and essential thrombocythemia patients: clinical implications. Exp Hematol. 2014;42(5):360–8.

    Article  CAS  PubMed  Google Scholar 

  80. Tefferi A, Vaidya R, Caramazza D, Finke C, Lasho T, Pardanani A. Circulating interleukin (IL)-8, IL-2R, IL-12, and IL-15 levels are independently prognostic in primary myelofibrosis: a comprehensive cytokine profiling study. J Clin Oncol. 2011;29(10):1356–63.

    Article  CAS  PubMed  Google Scholar 

  81. Emadi S, Clay D, Desterke C, et al. IL-8 and its CXCR1 and CXCR2 receptors participate in the control of megakaryocytic proliferation, differentiation, and ploidy in myeloid metaplasia with myelofibrosis. Blood. 2005;105(2):464–73.

    Article  CAS  PubMed  Google Scholar 

  82. Hermouet S, Godard A, Pineau D, et al. Abnormal production of interleukin (IL)-11 and IL-8 in polycythaemia vera. Cytokine. 2002;20(4):178–83.

    Article  CAS  PubMed  Google Scholar 

  83. Desterke C, Bilhou-Nabéra C, Guerton B, et al. FLT3-mediated p38-MAPK activation participates in the control of megakaryopoiesis in primary myelofibrosis. Cancer Res. 2011;71(8):2901–15.

    Article  CAS  PubMed  Google Scholar 

  84. Wehrle J, Seeger TS, Schwemmers S, Pfeifer D, Bulashevska A, Pahl HL. Transcription factor nuclear factor erythroid-2 mediates expression of the cytokine interleukin 8, a known predictor of inferior outcome in patients with myeloproliferative neoplasms. Haematologica. 2013;98(7):1073–80.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  85. Le Bousse-Kerdiles MC, Chevillard S, Charpentier A, et al. Differential expression of transforming growth factor-β, basic fibroblast growth factor, and their receptors in CD34+ hematopoietic progenitor cells from patients with myelofibrosis and myeloid metaplasia. Blood. 1996;88(12):4534–46.

    PubMed  Google Scholar 

  86. Campanelli R, Rosti V, Villani L, et al. Evaluation of the bioactive and total transforming growth factor β1 levels in primary myelofibrosis. Cytokine. 2011;53(1):100–6.

    Article  CAS  PubMed  Google Scholar 

  87. Le Bousse-Kerdiles MC, Martyre MC, Samson M. Cellular and molecular mechanisms underlying bone marrow and liver fibrosis: a review. Eur Cytokine Netw. 2008;19(2):69–80.

    PubMed  Google Scholar 

  88. Vannucchi AM, Bianchi L, Paoletti F, et al. A pathologic pathway linking thrombopoietin, GATA-1 and TGF-β1 in the development of myelofibrosis. Blood. 2005;105(9):3493–501.

    Article  CAS  PubMed  Google Scholar 

  89. Wang JC, Chang TH, Goldberg A, Novetsky AD, Lichter S, Lipton J. Quantitative analysis of growth factor production in the mechanism of fibrosis in agnogenic myeloid metaplasia. Exp Hematol. 2006;34(12):1617–23.

    Article  CAS  PubMed  Google Scholar 

  90. Badalucco S, Di Buduo CA, Campanelli R, et al. Involvement of TGFβ1 in autocrine regulation of proplatelet formation in healthy subjects and patients with primary myelofibrosis. Haematologica. 2013;98(4):514–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  91. Barbui T, Carobbio A, Finazzi G, et al. Elevated C-reactive protein is associated with shortened leukemia-free survival in patients with myelofibrosis. Leukemia. 2013;27(10):2084–6.

    Article  CAS  PubMed  Google Scholar 

  92. Barbui T, Carobbio A, Finazzi G, et al. Inflammation and thrombosis in essential thrombocythemia and polycythemia vera: different role of C-reactive protein and pentraxin 3. Haematologica. 2011;96(2):315–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  93. Tefferi A, Verstovsek S, Barosi G, et al. Pomalidomide is active in the treatment of anemia associated with myelofibrosis. J Clin Oncol. 2009;27(27):4563–9.

    Article  CAS  PubMed  Google Scholar 

  94. Centenara E, Guarnone R, Ippoliti G, Barosi G. Cyclosporin-A in severe refractory anemia of myelofibrosis with myeloid metaplasia: a preliminary report. Haematologica. 1998;83(7):622–6.

    CAS  PubMed  Google Scholar 

  95. Barosi G, Rosti V, Vannucchi AM. Therapeutic approaches in myelofibrosis. Expert Opin Pharmacother. 2011;12(10):1597–611.

    Article  CAS  PubMed  Google Scholar 

  96. Akhmetshina A, Palumbo K, Dees C, et al. Activation of canonical Wnt signalling is required for TGF-β-mediated fibrosis. Nat Commun. 2012;3:735.

    Article  PubMed Central  PubMed  Google Scholar 

  97. Tabarroki A, Lindner DJ, Visconte V, et al. Ruxolitinib leads to improvement of pulmonary hypertension in patients with myelofibrosis. Leukemia. 2014;10. The paper provides evidence that JAK1/JAK2 inhibitor ruxolitinib improves pulmonary hypertension associated with MF and reduces the level of inflammatory cytokines. This may be taken as evidence that pulmonary hypertension in MF has an inflammatory pathogenesis.

  98. Avanzini MA, Bernardo ME, Novara F, et al. Functional and genetic aberrations of in vitro-cultured marrow-derived mesenchymal stromal cells of patients with classical Philadelphia-negative myeloproliferative neoplasms. Leukemia. 2014.

  99. Silver RT, Kiladjian JJ, Hasselbalch HC. Interferon and the treatment of polycythemia vera, essential thrombocythemia and myelofibrosis. Expert Rev Hematol. 2013;6(1):49–58.

    Article  CAS  PubMed  Google Scholar 

  100. Hasselbalch HC, Riley CH. Statins in the treatment of polycythaemia vera and allied disorders: an antithrombotic and cytoreductive potential? Leuk Res. 2006;30(10):1217–25.

    Article  CAS  PubMed  Google Scholar 

  101. Mascarenhas J, Li T, Sandy L, et al. Anti-transforming growth factor-β therapy in patients with myelofibrosis. Leuk Lymphoma. 2014;55(2):450–2.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by a grant from Associazione Italiana per la Ricerca sul Cancro (AIRC, Milano) “Special Program Molecular Clinical Oncology 5x1000” to AGIMM (AIRC-Gruppo Italiano Malattie Mieloproliferative). A detailed description of the AGIMM project is available at http://www.progettoagimm.it.

Compliance with Ethics Guidelines

ᅟ

Conflict of Interest

Dr. Giovanni Barosi declares that he has no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Author information

Authors and Affiliations

  1. Center of the Study of Myelofibrosis, IRCCS Policlinico S. Matteo Foundation, Viale Golgi 19, 27100, Pavia, Italy

    Giovanni Barosi

Authors
  1. Giovanni Barosi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Giovanni Barosi.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Barosi, G. An Immune Dysregulation in MPN. Curr Hematol Malig Rep 9, 331–339 (2014). https://doi.org/10.1007/s11899-014-0227-0

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11899-014-0227-0

Keywords

Search

Navigation