Skip to main content

Advertisement

Log in

The inflammatory microenvironment in MDS

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

Myelodysplastic syndromes (MDS) are a collection of pre-malignancies characterized by impaired proliferation and differentiation of hematopoietic stem cells and a tendency to evolve into leukemia. Among MDS’s pathogenic mechanisms are genetic, epigenetic, apoptotic, differentiation, and cytokine milieu abnormalities. Inflammatory changes are a prominent morphologic feature in some cases, with increased populations of plasma cells, mast cells, and lymphocytes in bone marrow aspirates. Accumulating evidence suggests that the bone marrow microenvironment contributes to MDS disease pathology, with microenvironment alterations and abnormality preceding, and facilitating clonal evolution in MDS patients. In this review, we focus on the inflammatory changes involved in the pathology of MDS, with an emphasis on immune dysfunction, stromal microenvironment, and cytokine imbalance in the microenvironment as well as activation of innate immune signaling in MDS patients. A better understanding of the mechanism of MDS pathophysiology will be beneficial to the development of molecular-targeted therapies in the future.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. Virdis A, Dell’Agnello U, Taddei S (2014) Impact of inflammation on vascular disease in hypertension. Maturitas 78(3):179–183

    Article  CAS  PubMed  Google Scholar 

  2. Wang YH, Liu YJ (2009) Thymic stromal lymphopoietin, OX40-ligand, and interleukin-25 in allergic responses. Clin Exp Allergy 39(6):798–806

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Chen X et al (2013) Induction of myelodysplasia by myeloid-derived suppressor cells. J Clin Invest 123(11):4595–4611

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Ueda Y, Kondo M, Kelsoe G (2005) Inflammation and the reciprocal production of granulocytes and lymphocytes in bone marrow. J Exp Med 201(11):1771–1780

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Ganan-Gomez I et al (2014) Overexpression of miR-125a in myelodysplastic syndrome CD34+ cells modulates NF-kappaB activation and enhances erythroid differentiation arrest. PLoS One 9(4):e93404

    Article  PubMed Central  PubMed  Google Scholar 

  6. Balin SJ et al (2011) Myelodysplastic syndrome presenting as generalized granulomatous dermatitis. Arch Dermatol 147(3):331–335

    Article  PubMed  Google Scholar 

  7. Mekinian A et al (2014) Inflammatory arthritis in patients with myelodysplastic syndromes: a multicenter retrospective study and literature review of 68 cases. Medicine (Baltimore) 93(1):1–10

    Article  CAS  Google Scholar 

  8. Gabrilovich DI, Nagaraj S (2009) Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 9(3):162–174

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Kusmartsev S, Gabrilovich DI (2006) Role of immature myeloid cells in mechanisms of immune evasion in cancer. Cancer Immunol Immunother 55(3):237–245

    Article  PubMed Central  PubMed  Google Scholar 

  10. Vogl T et al (2007) Mrp8 and Mrp14 are endogenous activators of Toll-like receptor 4, promoting lethal, endotoxin-induced shock. Nat Med 13(9):1042–1049

    Article  CAS  PubMed  Google Scholar 

  11. Ehrchen JM et al (2009) The endogenous Toll-like receptor 4 agonist S100A8/S100A9 (calprotectin) as innate amplifier of infection, autoimmunity, and cancer. J Leukoc Biol 86(3):557–566

    Article  CAS  PubMed  Google Scholar 

  12. Sade-Feldman M et al (2013) Tumor necrosis factor-alpha blocks differentiation and enhances suppressive activity of immature myeloid cells during chronic inflammation. Immunity 38(3):541–554

    Article  CAS  PubMed  Google Scholar 

  13. Bouchliou I et al (2011) Th17 and Foxp3(+) T regulatory cell dynamics and distribution in myelodysplastic syndromes. Clin Immunol 139(3):350–359

    Article  CAS  PubMed  Google Scholar 

  14. Kordasti SY et al (2009) IL-17-producing CD4(+) T cells, pro-inflammatory cytokines and apoptosis are increased in low risk myelodysplastic syndrome. Br J Haematol 145(1):64–72

    Article  CAS  PubMed  Google Scholar 

  15. Mailloux AW, Epling-Burnette PK (2013) Effector memory regulatory T-cell expansion marks a pivotal point of immune escape in myelodysplastic syndromes. Oncoimmunology 2(2):e22654

    Article  PubMed Central  PubMed  Google Scholar 

  16. Mailloux AW et al (2012) Expansion of effector memory regulatory T cells represents a novel prognostic factor in lower risk myelodysplastic syndrome. J Immunol 189(6):3198–3208

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Zou JX et al (2009) Altered naive and memory CD4+ T-cell homeostasis and immunosenescence characterize younger patients with myelodysplastic syndrome. Leukemia 23(7):1288–1296

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Kordasti SY et al (2007) CD4+ CD25high Foxp3+ regulatory T cells in myelodysplastic syndrome (MDS). Blood 110(3):847–850

    Article  CAS  PubMed  Google Scholar 

  19. Sloand EM et al (2005) Preferential suppression of trisomy 8 compared with normal hematopoietic cell growth by autologous lymphocytes in patients with trisomy 8 myelodysplastic syndrome. Blood 106(3):841–851

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Benesch M et al (2003) Expression of FLIP(Long) and FLIP(Short) in bone marrow mononuclear and CD34+ cells in patients with myelodysplastic syndrome: correlation with apoptosis. Leukemia 17(12):2460–2466

    Article  CAS  PubMed  Google Scholar 

  21. Kochenderfer JN et al (2002) Loss of T-lymphocyte clonal dominance in patients with myelodysplastic syndrome responsive to immunosuppression. Blood 100(10):3639–3645

    Article  CAS  PubMed  Google Scholar 

  22. Epling-Burnette PK et al (2007) Reduced natural killer (NK) function associated with high-risk myelodysplastic syndrome (MDS) and reduced expression of activating NK receptors. Blood 109(11):4816–4824

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Epling-Burnette PK et al (2007) Prevalence and clinical association of clonal T-cell expansions in Myelodysplastic Syndrome. Leukemia 21(4):659–667

    CAS  PubMed  Google Scholar 

  24. Sloand EM, Rezvani K (2008) The role of the immune system in myelodysplasia: implications for therapy. Semin Hematol 45(1):39–48

    Article  CAS  PubMed  Google Scholar 

  25. Olnes MJ, Sloand EM (2011) Targeting immune dysregulation in myelodysplastic syndromes. JAMA 305(8):814–819

    Article  CAS  PubMed  Google Scholar 

  26. Raaijmakers MH (2011) Niche contributions to oncogenesis: emerging concepts and implications for the hematopoietic system. Haematologica 96(7):1041–1048

    Article  PubMed Central  PubMed  Google Scholar 

  27. Raaijmakers MH et al (2010) Bone progenitor dysfunction induces myelodysplasia and secondary leukaemia. Nature 464(7290):852–857

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Flores-Figueroa E et al (2005) Mesenchymal stem cells in myelodysplastic syndromes: phenotypic and cytogenetic characterization. Leuk Res 29(2):215–224

    Article  CAS  PubMed  Google Scholar 

  29. Flores-Figueroa E et al (2008) Functional analysis of myelodysplastic syndromes-derived mesenchymal stem cells. Leuk Res 32(9):1407–1416

    Article  CAS  PubMed  Google Scholar 

  30. Geyh S et al (2013) Insufficient stromal support in MDS results from molecular and functional deficits of mesenchymal stromal cells. Leukemia 27(9):1841–1851

    Article  CAS  PubMed  Google Scholar 

  31. Zhao ZG et al (2012) Functional characteristics of mesenchymal stem cells derived from bone marrow of patients with myelodysplastic syndromes. Cancer Lett 317(2):136–143

    Article  CAS  PubMed  Google Scholar 

  32. Zhao Z et al (2012) The different immunoregulatory functions of mesenchymal stem cells in patients with low-risk or high-risk myelodysplastic syndromes. PLoS One 7(9):e45675

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Campioni D et al (2006) Immunophenotypic heterogeneity of bone marrow-derived mesenchymal stromal cells from patients with hematologic disorders: correlation with bone marrow microenvironment. Haematologica 91(3):364–368

    PubMed  Google Scholar 

  34. Lopez-Villar O et al (2009) Both expanded and uncultured mesenchymal stem cells from MDS patients are genomically abnormal, showing a specific genetic profile for the 5q- syndrome. Leukemia 23(4):664–672

    Article  CAS  PubMed  Google Scholar 

  35. Varga G et al (2007) Inappropriate Notch activity and limited mesenchymal stem cell plasticity in the bone marrow of patients with myelodysplastic syndromes. Pathol Oncol Res 13(4):311–319

    Article  CAS  PubMed  Google Scholar 

  36. Aanei CM et al (2012) Intrinsic growth deficiencies of mesenchymal stromal cells in myelodysplastic syndromes. Stem Cells Dev 21(10):1604–1615

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Walkley CR et al (2007) A microenvironment-induced myeloproliferative syndrome caused by retinoic acid receptor gamma deficiency. Cell 129(6):1097–1110

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Walkley CR et al (2007) Rb regulates interactions between hematopoietic stem cells and their bone marrow microenvironment. Cell 129(6):1081–1095

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Li L, Neaves WB (2006) Normal stem cells and cancer stem cells: the niche matters. Cancer Res 66(9):4553–4557

    Article  CAS  PubMed  Google Scholar 

  40. Sneddon JB, Werb Z (2007) Location, location, location: the cancer stem cell niche. Cell Stem Cell 1(6):607–611

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. Serio B et al (2014) Immunological derangement in hypocellular myelodysplastic syndromes. Transl Med UniSa 8:31–42

    PubMed Central  CAS  PubMed  Google Scholar 

  42. Li X et al (2010) The helix-loop-helix transcription factor TWIST is dysregulated in myelodysplastic syndromes. Blood 116(13):2304–2314

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  43. da Costa SV et al (2010) The role of p38 mitogen-activated protein kinase in serum-induced leukemia inhibitory factor secretion by bone marrow stromal cells from pediatric myelodysplastic syndromes. Leuk Res 34(4):507–512

    Article  PubMed  Google Scholar 

  44. Navas T et al (2008) Inhibition of p38alpha MAPK disrupts the pathological loop of proinflammatory factor production in the myelodysplastic syndrome bone marrow microenvironment. Leuk Lymphoma 49(10):1963–1975

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. Fessenden JD et al (2001) Ryanodine receptor point mutant E4032A reveals an allosteric interaction with ryanodine. Proc Natl Acad Sci USA 98(5):2865–2870

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Wetzler M et al (1995) Cytokine expression in adherent layers from patients with myelodysplastic syndrome and acute myelogenous leukemia. Leuk Res 19(1):23–34

    Article  CAS  PubMed  Google Scholar 

  47. Weimar IS et al (1998) Hepatocyte growth factor/scatter factor (HGF/SF) affects proliferation and migration of myeloid leukemic cells. Leukemia 12(8):1195–1203

    Article  CAS  PubMed  Google Scholar 

  48. Marcondes AM et al (2008) Dysregulation of IL-32 in myelodysplastic syndrome and chronic myelomonocytic leukemia modulates apoptosis and impairs NK function. Proc Natl Acad Sci USA 105(8):2865–2870

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  49. Selleri C et al (2002) Effects of cyclosporine on hematopoietic and immune functions in patients with hypoplastic myelodysplasia: in vitro and in vivo studies. Cancer 95(9):1911–1922

    Article  CAS  PubMed  Google Scholar 

  50. Sato T et al (1995) Hematopoietic inhibition by interferon-gamma is partially mediated through interferon regulatory factor-1. Blood 86(9):3373–3380

    CAS  PubMed  Google Scholar 

  51. Navas TA et al (2006) Inhibition of overactivated p38 MAPK can restore hematopoiesis in myelodysplastic syndrome progenitors. Blood 108(13):4170–4177

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  52. Sokol L et al (2013) Randomized, dose-escalation study of the p38alpha MAPK inhibitor SCIO-469 in patients with myelodysplastic syndrome. Leukemia 27(4):977–980

    Article  CAS  PubMed  Google Scholar 

  53. Bar M et al (2008) Gene expression patterns in myelodyplasia underline the role of apoptosis and differentiation in disease initiation and progression. Transl Oncogenomics 3:137–149

    PubMed Central  CAS  PubMed  Google Scholar 

  54. Chen G et al (2004) Distinctive gene expression profiles of CD34 cells from patients with myelodysplastic syndrome characterized by specific chromosomal abnormalities. Blood 104(13):4210–4218

    Article  CAS  PubMed  Google Scholar 

  55. Maratheftis CI et al (2007) Toll-like receptor-4 is up-regulated in hematopoietic progenitor cells and contributes to increased apoptosis in myelodysplastic syndromes. Clin Cancer Res 13(4):1154–1160

    Article  CAS  PubMed  Google Scholar 

  56. Wei Y et al (2013) Toll-like receptor alterations in myelodysplastic syndrome. Leukemia 27(9):1832–1840

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  57. Dimicoli S et al (2013) Overexpression of the toll-like receptor (TLR) signaling adaptor MYD88, but lack of genetic mutation, in myelodysplastic syndromes. PLoS One 8(8):e71120

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  58. Rhyasen GW et al (2013) Targeting IRAK1 as a therapeutic approach for myelodysplastic syndrome. Cancer Cell 24(1):90–104

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  59. Rhyasen GW, Bolanos L, Starczynowski DT (2013) Differential IRAK signaling in hematologic malignancies. Exp Hematol 41(12):1005–1007

    Article  CAS  PubMed  Google Scholar 

  60. Hofmann WK et al (2002) Characterization of gene expression of CD34+ cells from normal and myelodysplastic bone marrow. Blood 100(10):3553–3560

    Article  CAS  PubMed  Google Scholar 

  61. Gondek LP et al (2008) Chromosomal lesions and uniparental disomy detected by SNP arrays in MDS, MDS/MPD, and MDS-derived AML. Blood 111(3):1534–1542

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  62. Starczynowski DT et al (2008) High-resolution whole genome tiling path array CGH analysis of CD34+ cells from patients with low-risk myelodysplastic syndromes reveals cryptic copy number alterations and predicts overall and leukemia-free survival. Blood 112(8):3412–3424

    Article  CAS  PubMed  Google Scholar 

  63. Fang J et al (2012) Cytotoxic effects of bortezomib in myelodysplastic syndrome/acute myeloid leukemia depend on autophagy-mediated lysosomal degradation of TRAF6 and repression of PSMA1. Blood 120(4):858–867

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  64. Starczynowski DT et al (2010) Identification of miR-145 and miR-146a as mediators of the 5q- syndrome phenotype. Nat Med 16(1):49–58

    Article  CAS  PubMed  Google Scholar 

  65. Boldin MP et al (2011) miR-146a is a significant brake on autoimmunity, myeloproliferation, and cancer in mice. J Exp Med 208(6):1189–1201

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  66. Zhao JL et al (2011) NF-kappaB dysregulation in microRNA-146a-deficient mice drives the development of myeloid malignancies. Proc Natl Acad Sci USA 108(22):9184–9189

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  67. Fang J et al (2014) Myeloid malignancies with chromosome 5q deletions acquire a dependency on an intrachromosomal NF-kappaB gene network. Cell Rep 8(5):1328–1338

    Article  CAS  PubMed  Google Scholar 

  68. Kerbauy DM et al (2005) NF-kappaB and FLIP in arsenic trioxide (ATO)-induced apoptosis in myelodysplastic syndromes (MDSs). Blood 106(12):3917–3925

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  69. Fabre C et al (2007) NF-kappaB inhibition sensitizes to starvation-induced cell death in high-risk myelodysplastic syndrome and acute myeloid leukemia. Oncogene 26(28):4071–4083

    Article  CAS  PubMed  Google Scholar 

  70. Pyatt DW et al (1999) An essential role for NF-kappaB in human CD34(+) bone marrow cell survival. Blood 93(10):3302–3308

    CAS  PubMed  Google Scholar 

  71. Wei Y et al (2013) Global H3K4me3 genome mapping reveals alterations of innate immunity signaling and overexpression of JMJD3 in human myelodysplastic syndrome CD34+ cells. Leukemia 27(11):2177–2186

    Article  CAS  PubMed  Google Scholar 

  72. Rupec RA et al (2005) Stroma-mediated dysregulation of myelopoiesis in mice lacking I kappa B alpha. Immunity 22(4):479–491

    Article  CAS  PubMed  Google Scholar 

  73. Starczynowski DT, Karsan A (2010) Innate immune signaling in the myelodysplastic syndromes. Hematol Oncol Clin North Am 24(2):343–359

    Article  PubMed  Google Scholar 

  74. Sloand EM et al (2008) Factors affecting response and survival in patients with myelodysplasia treated with immunosuppressive therapy. J Clin Oncol 26(15):2505–2511

    Article  PubMed  Google Scholar 

  75. Lim ZY et al (2007) Low IPSS score and bone marrow hypocellularity in MDS patients predict hematological responses to antithymocyte globulin. Leukemia 21(7):1436–1441

    Article  CAS  PubMed  Google Scholar 

  76. Stadler M et al (2004) A prospective, randomised, phase II study of horse antithymocyte globulin vs rabbit antithymocyte globulin as immune-modulating therapy in patients with low-risk myelodysplastic syndromes. Leukemia 18(3):460–465

    Article  CAS  PubMed  Google Scholar 

  77. Steensma DP et al (2003) Antithymocyte globulin has limited efficacy and substantial toxicity in unselected anemic patients with myelodysplastic syndrome. Blood 101(6):2156–2158

    Article  CAS  PubMed  Google Scholar 

  78. List A et al (2006) Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med 355(14):1456–1465

    Article  CAS  PubMed  Google Scholar 

  79. Fenaux P et al (2009) Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol 10(3):223–232

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  80. Deeg HJ et al (2002) Soluble TNF receptor fusion protein (etanercept) for the treatment of myelodysplastic syndrome: a pilot study. Leukemia 16(2):162–164

    Article  CAS  PubMed  Google Scholar 

  81. Raza A et al (2001) Thalidomide produces transfusion independence in long-standing refractory anemias of patients with myelodysplastic syndromes. Blood 98(4):958–965

    Article  CAS  PubMed  Google Scholar 

  82. Deeg HJ et al (2004) Hematologic responses of patients with MDS to antithymocyte globulin plus etanercept correlate with improved flow scores of marrow cells. Leuk Res 28(11):1177–1180

    Article  PubMed  Google Scholar 

  83. Scott BL et al (2010) Anti-thymocyte globulin plus etanercept as therapy for myelodysplastic syndromes (MDS): a phase II study. Br J Haematol 149(5):706–710

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  84. Jaiswal S et al (2014) Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med 371(26):2488–2498

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

L. Yang was supported by a Grant from Tianjin Natural Science Fund (14JCYBJC12100). EAE is supported by NCI K01CA187020.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Sheng Wei.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yang, L., Qian, Y., Eksioglu, E. et al. The inflammatory microenvironment in MDS. Cell. Mol. Life Sci. 72, 1959–1966 (2015). https://doi.org/10.1007/s00018-015-1846-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-015-1846-x

Keywords

Navigation