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Myelodysplastic syndromes: an update on molecular pathology

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  • Molecular and Cellular Biology of Cancer
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Abstract

The myelodysplastic syndromes (MDS) are a heterogeneous group of myeloid disorders characterised by impaired peripheral blood cell production due to bone marrow dysplasia affecting one or more of the major myeloid cell lines. MDS are one of five major categories of myeloid neoplasms according to the World Health Organization (WHO) classification system for haematological cancers. Given their cytological and cytogenetic heterogeneity, these diseases probably constitute a group of molecularly distinct entities with variable degrees of ineffective haematopoiesis and susceptibility to leukaemic transformation. Recent studies provide some insights into the physiopathology of MDS. In the early stages, one mechanism contributing to hypercellular marrow and peripheral blood cytopenia is a significant increase in programmed cell death (apoptosis) in haematopoietic cells. Furthermore, altered responses in relation to cytokines, the immune system and bone marrow stroma also contribute to the disease phenotype. Deletions of chromosome 5q31–q32 are the most common recurring cytogenetic abnormalities detected in MDS. The 5q- syndrome is a new entity recognised in the WHO classification since 2001 and is associated with a good prognosis. Haploinsufficiency of multiple genes mapping to the common deleted region at 5q31–32 may contribute to the pathogenesis of 5q- syndrome and other MDS with 5q- deletion. Many studies have demonstrated that altered DNA methylation and histone acetylation can alter gene transcription. Abnormal methylation of transcription promoter sites is universal in patients with MDS, and the number of involved loci is increased in high-risk disease and secondary leukaemias. A better understanding of the pathogenesis of MDS can contribute to the development of new treatments such as hypomethylating drugs, immunomodulatory agents such as lenalidomide, and immunosuppressive drugs aimed at reversing the specific alteration that results in improvement in patients with MDS.

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References

  1. Bennett JM, Catovsky D, Daniel MT et al (1982) Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 51:189–199

    CAS  PubMed  Google Scholar 

  2. Vardiman JW, Harris NL, Brunning RD (2002) The World Health Organization (WHO) classification of the myeloid neoplasms. Blood 100:2292–2302

    Article  CAS  PubMed  Google Scholar 

  3. Vardiman JW, Thiele J, Arber DA et al (2009) The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood 5:937–951

    Article  Google Scholar 

  4. Rollinson DE, Howlader N, Smith MT et al (2008) Epidemiology of myelodysplastic syndromes and chronic myeloproliferative disorders in the United States, 2001–2004, using data from the NAACCR and SEER programs. Blood 112:45–52

    Article  Google Scholar 

  5. Strom SS, Gu Y, Gruschkus SK et al (2005) Risk factors of myelodysplastic syndromes: a case control study. Leukemia 19:1912–1918

    Article  CAS  PubMed  Google Scholar 

  6. Owen C, Barnett M, Fitzgibbon J (2008) Familial myelodysplasia and acute myeloid leukemia: a review. Br J Haematol 140:123–132

    Article  CAS  PubMed  Google Scholar 

  7. Pedersen-Bjergaard J, Andersen MK, Christiansen DH, Nerlov C (2002) Genetic pathways in therapy-related myelodysplasia and acute myeloid leukemia. Blood 99:1909–1912

    Article  CAS  PubMed  Google Scholar 

  8. Mufti GJ (1992) Chromosomal deletions in the myelodysplastic syndrome. Leuk Res 16:35–41

    Article  CAS  PubMed  Google Scholar 

  9. Rigolin GM, Bigoni R, Milani R et al (2001) Clinical importance of interphase cytogenetics detecting occult chromosome lesions in myelodysplastic syndromes with normal karyotype. Leukemia 15:1841–1847

    CAS  PubMed  Google Scholar 

  10. Fenaux P (2001) Chromosome and molecular abnormalities in myelodysplastic syndromes. Int J Haematol 12:1841–1847

    Google Scholar 

  11. Mhawech P, Saleem A (2001) Myelodysplastic syndrome review of the cytogenetic and molecular data. Crit Rev Oncol Hematol 73:429–437

    Google Scholar 

  12. Bennet JM, Komorokj R, Kouldes PA (2004) The myelodysplastic syndromes. In: Abeloff MD, Armitage JO, Niederhuber JE et al (eds) Clinical oncology, 3rd edn. Elsevier, Philadelphia, PA, pp 2849–2882

    Google Scholar 

  13. Shali W, Helias C, Foher C et al (2006) Cytogenetic studies of a series of 43 consecutive secondary myelodysplastic syndromes/acute myeloid leukemias conventional cytogenetics FISH and multiplex FISH. Cancer Genet Cytogenet 168: 133–145

    Article  CAS  PubMed  Google Scholar 

  14. Greenberg P, Cox C, LeBeau MM et al (1997) International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 89: 2079–2088

    CAS  PubMed  Google Scholar 

  15. Macovati L, Germing U, Kuendgen A et al (2007) Time-dependent prognostic scoring system for predicting survival and leukemic evolution in myelodysplastic syndromes. J Clin Oncol 25:3503–3510

    Article  Google Scholar 

  16. Raza A, Gezer S, Mundle S et al (1997) Apoptosis in bone marrow biopsy samples involving stromal and hematopoietic cells in 50 patients with myelodysplastic syndromes. Blood 89:1690–1700

    Google Scholar 

  17. Hellstrom-Lindberg E, Kanter-Lewensohn L, Ost A (1997) Morphological changes and apoptosis in bone marrow from patients with myelodysplastic syndromes treated with granulocyte-CSF and erythropoietin. Leuk Res 21:415–425

    Article  CAS  PubMed  Google Scholar 

  18. Parker JE, Fishlock KL, Mijovic A et al (1998) ’Low-risk’ myelodysplastic syndromes is associated with excessive apoptosis and increased ratio of pro- versus anti-apoptotic bcl-2-related proteins. Br J Haematol 103:1075–1082

    Article  CAS  PubMed  Google Scholar 

  19. Parker JE, Mufti GJ, Rasool F et al (2000) The role of apoptosis, proliferation, and the Bcl-2-related proteins in the myelodysplastic syndromes and acute myeloid leukemia secondary to MDS. Blood 96:3932–3938

    CAS  PubMed  Google Scholar 

  20. Tsoplou P, Kouraklis-Symeonidis A, Thanopoulou E et al (1999) Apoptosis in patients with myelodysplastic syndromes: differential involvement of marrow cells in ‘good’ versus ‘poor’ prognosis patients and correlation with apoptosis-related genes. Leukemia 13:1554–156

    Article  CAS  PubMed  Google Scholar 

  21. Greenberg PL, Sun Z, Miller KB et al (2009) Treatment of myelodysplastic syndromes patients with erythropoietin with or with-out granulocyte colony-stimulating factor: results of a prospective randomized phase III trial by the Eastern Cooperative Oncology Group (E1996). Blood 114:2393–2400

    Article  CAS  PubMed  Google Scholar 

  22. Economopoulou C, Pappa V, Papageorgiou S et al (2010) Cell cycle and apoptosis regulatory gene expression in bone marrow of patients with de novo myelodysplastic syndromes. Ann Hematol 89:349–358

    Article  CAS  PubMed  Google Scholar 

  23. Economopoulou C, Pappa V, Kontsioti F et al (2008) Analysis of apoptosis regulatory genes expression in the bone marrow of adult de novo myelodysplastic syndromes. Leukemia Res 32:61–69

    Article  CAS  Google Scholar 

  24. Gersuk GM, Lee JE, Beckham CA et al (1996) Fas (CD95) receptor and Fas-ligand expression in bone marrow cells from patients with myelodysplastic syndrome. Blood 88:1122–1123

    CAS  PubMed  Google Scholar 

  25. Benesch M, Platzbecker U, Ward J et al (2003) Expression of FLIPlong and FLIPshort in bone marrow mononuclear and CD34+ cells in patients with myelodysplastic syndrome: correlation with apoptosis. Leukemia 17:2460–2466

    Article  CAS  PubMed  Google Scholar 

  26. De Melo Campos P, Traina F, da Silva Santos Duarte A et al (2007) Reduced expression of FLIP SHORT in bone marrow of low risk myelodysplastic syndrome. Leuk Res 31:853–857

    Article  PubMed  Google Scholar 

  27. Schmidt-Mende J, Tehranchi R, Forsblom AM et al (2001) Granulocyte colony-stimulating factor inhibits Fas-triggered apoptosis in bone marrow cells isolated from patients with refractory anemia with ringed sideroblasts. Leukemia 15:742–751

    Article  CAS  PubMed  Google Scholar 

  28. Kerbauy DB, Deeg HJ (2007) Apoptosis and antiapoptotic mechanisms in the progression of MDS. Exp Hematol 35:1739–1746

    Article  CAS  PubMed  Google Scholar 

  29. Green DR, Reed JC (1998) Mitochondria and apoptosis. Science 281:1309–1312

    Article  CAS  PubMed  Google Scholar 

  30. Hengartner MO (2000) The biochemistry of apoptosis. Nature 407:770–776

    Article  CAS  PubMed  Google Scholar 

  31. Tehranchi R, Fadeel B, Forsblom A et al (2003) Granulocyte colony-stimulating factor inhibits spontaneous cytochrome c release and mitochondria- dependent apoptosis of myelodysplastic syndrome. Blood 101:1080–1086

    Article  CAS  PubMed  Google Scholar 

  32. Tehranchi R, Fadeel B, Schmidt-Mende J et al (2005) Antiapoptotic role of growth factors in the myelodysplastic syndromes: concordance between in vitro and in vivo observations. Clin Cancer Res 11:6291–6299

    Article  CAS  PubMed  Google Scholar 

  33. Fadeel B, Orrenius S, Zhivotovsky B (2000) The most unkindest cut of all: on the multiple roles of mammalian caspases. Leukemia 14:1514–1525

    Article  CAS  PubMed  Google Scholar 

  34. Braun T, Carvalho G, Coquelle A et al (2006) NF-KB constitutes a potential therapeutic target in high-risk myelodysplastic syndrome. Blood 107:1156–1165

    Article  CAS  PubMed  Google Scholar 

  35. Barkett M, Gilmore TD (1999) Control of apoptosis by Rel/NF-kappaB transcription factor. Oncogene 18:6910–6924

    Article  CAS  PubMed  Google Scholar 

  36. Kerbaury DB, Lesnikov V, Abbasi N et al (2005) NF-κB and FLIP in arsenic trioxide (ATO)-induced apoptosis in myelodysplastic syndromes. Blood 106:3917–3925

    Article  Google Scholar 

  37. Bernasconi P (2008) Molecular pathways in myelodysplastic syndromes and acute myeloid leukemia: relationships and distinctions-a review. Br J Haematol 142:695–708

    Article  CAS  PubMed  Google Scholar 

  38. Stirewalt DL, Mhyre AJ, Marcondes M et al (2008) Tumour necrosis factor-induced gene expression in human marrow stroma: clues to the pathophysiology of MDS? Br J Haematol 140:444–453

    Article  CAS  PubMed  Google Scholar 

  39. Marcondes MA, Mhyre AJ, Stirewalt DL et al (2008) Dysregulation of IL-32 in myelodysplastic syndrome and chronic myelomonocytic leukemia modulates apoptosis and impairs NK function. Proc Natl Acad Sci U S A 105:2865–2870

    Article  CAS  PubMed  Google Scholar 

  40. Sloand EM, Wu CO, Greemberg P et al (2008) Factors affecting response and survival in patients with myelodysplasia treated with immunosuppressive therapy. J Clin Oncol 26:2505–2511

    Article  PubMed  Google Scholar 

  41. Fozza C, Contini S, Galleu A et al (2009) Patients with myelodysplastic syndromes display several T-cell expansions which are mostly polyclonal in the CD4(+) subset and oligoclonal in the CD8(+) subset. Exp Hematol 37:947–955

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  43. Sloand EM, Mainwaring L, Fuhrer M 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 106:841–851

    Article  CAS  PubMed  Google Scholar 

  44. Kotsiannidis I, Bouchliou I, Nakou E et al (2009) Kinetics, function and bone marrow trafficking of CD4+, CD25+ FOXP3+ regulatory T cells in myelodysplastic syndromes. Leukemia 23:510–518

    Article  Google Scholar 

  45. Sole F, Espinet B, Sanz GF et al (2000) Incidence, characterization and prognostic significance of chromosomal abnormalities in 640 patients with primary myelodysplastic syndromes. Grupo Cooperativo Español de Citogenética Hematológica. Br J Haematol 108:346–356

    Article  CAS  PubMed  Google Scholar 

  46. Ebert BL (2009) Deletion 5q in myelodysplastic syndrome: a paradigm for the study of hemizygous deletions in cancer. Leukemia 23:1252–1256

    Article  CAS  PubMed  Google Scholar 

  47. Pedersen B (1998) 5q(-) survival: importance of gender and deleted 5q bands and survival analysis based on 324 published cases. Leuk Lymphoma 31:325–334

    CAS  PubMed  Google Scholar 

  48. Lai F, Godley LA, Joslin J et al (2001) Transcript map and comparative analysis of the 1.5-Mb commonly deleted segment of human 5q31 in malignant myeloid disease with a del (5q). Genomics 71:235–245

    Article  CAS  PubMed  Google Scholar 

  49. Boultwood J, Pellagatti A, Cattan H et al (2007) Gene expression profiling of CD34+ cells in pa tients with the 5q- syndrome. Br J Haematol 139: 578–589

    Article  CAS  PubMed  Google Scholar 

  50. Shannon KM, Le Beau MM (2008) Cancer: hay in a hay-stack. Nature 451:252–253

    Article  CAS  PubMed  Google Scholar 

  51. Ebert BL, Pretz J, Bosco J et al (2008) Identification of RPS14 as a 5q- syndrome gene by RNA interference screen. Nature 451:335–339

    Article  CAS  PubMed  Google Scholar 

  52. Pellagatti A, Jädersten M, Forsblom AM et al (2007) Lenalidomide inhibits the malignant clone and up-regulates the SPARC gene mapping to the commonly deleted region in 5q- syndrome patients. Proc Natl Acad Sci U S A 104:11406–11411

    Article  CAS  PubMed  Google Scholar 

  53. Joslin JM, Fernald AA, Tennant TR et al (2007) Haploinsufficiency of EGR1, a candidate gene in the del (5q), leads to the development of myeloid disorders. Blood 110:719–726

    Article  CAS  PubMed  Google Scholar 

  54. Liu TX, Becker MW, Jelinek J et al (2007) Chromosome 5q deletion and epigenetic suppression of gene encoding alpha-catenin (CTNNA1) in myeloid cell transformation. Nat Med 13:78–83

    Article  PubMed  Google Scholar 

  55. Wei S, Chen X, Rocha K et al (2009) A critical role for phosphatase haplodeficiency in the selective suppression of deletion 5q MDS by lenalidomida. Proc Natl Acad Sci U S A 106:12974–12979

    Article  CAS  PubMed  Google Scholar 

  56. Wang J, Fernald AA, Anastasi J et al (2010) Haploinsufficiency of Apc leads to ineffective hematopoiesis. Blood 115:3481–3488

    Article  CAS  PubMed  Google Scholar 

  57. Grisendi S, Bernardi R, Rossi M et al (2005) Role of nucleophosmin in embryonic development and tumorigenesis. Nature 437:147–153

    Article  CAS  PubMed  Google Scholar 

  58. Dana SL, Chang S, Wasmunth JJ (1985) Synthesis and incorporation of human ribosomal protein S14 into functional ribosomes in human-Chinese hamster cell hybrids containing human chromosome 5: human RPS14 gene is the structural gene for ribosomal protein S14. Somat Cell Mol Genet 11:625–631

    Article  CAS  PubMed  Google Scholar 

  59. Pellagatti A, Hellström-Lindberg E, Giagounidis A et al (2008) Haploinsufficiency of RPS14 in 5q- syndrome is associated with deregulation of ribosomal- and translation-related genes. Br J Haematol 142:57–64

    Article  CAS  PubMed  Google Scholar 

  60. Mohamendali A, Mufti GL (2008) Van-den Berghe’s 5q- syndrome in 2008. Br J Haematol 144: 157–168

    Article  Google Scholar 

  61. Narla A, Ebert BL (2010) Ribosomopathies: human disorders of ribosome dysfunction. Blood 115:3196–3205

    Article  CAS  PubMed  Google Scholar 

  62. Yiu GK, Chan WY, Ng SW et al (2001) SPARC (secreted protein acidic and rich in cysteine) induces apoptosis in ovarian cancer cells. Am J Pathol 159:609–622

    CAS  PubMed  Google Scholar 

  63. DiMartino JF, Lacayo NJ, Varadi M et al (2006) Low or absent SPARC expression in acute myeloid leukaemia with MLL rearrangements is associated with sensitivity to growth inhibition by exogenous SPARC protein. Leukemia 20:426–432

    Article  CAS  PubMed  Google Scholar 

  64. List A, Dewald G, Bennett J et al (2006) Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med 355: 1456–1465

    Article  CAS  PubMed  Google Scholar 

  65. Min IM, Pietramaggiori G, Kim FS et al (2008) The transcription factor EGR1 controls both the proliferation and localization of hematopoietic stem cells. Cell Stem Cell 2:380–391

    Article  CAS  PubMed  Google Scholar 

  66. Fodde R, Smits R, Clevers H (2001) APC, signal transduction and genetic instability in colorectal cancer. Nat Rev Cancer 1:55–67

    Article  CAS  PubMed  Google Scholar 

  67. Falini B, Mecucci C, Tiacci E, et al (2005) Cytoplasmic nucleophosmin in acute myelogenous leukemia with normal karyotipe. N Engl J Med 352:254–266

    Article  CAS  PubMed  Google Scholar 

  68. Sportoletti P, Grisendi S, Majid SM et al (2008) Nmp1 is a haploinsufficient suppressor of myeloid and lymphoid malignancies in the mouse. Blood 111:3859–3862

    Article  CAS  PubMed  Google Scholar 

  69. Robertson KD, Woffe AP (2000) DNA methylation in health and disease. Nat Rev Genet 1:11–19

    Article  CAS  PubMed  Google Scholar 

  70. Rice JC, Allis CD (2001) Code of silence. Nature 414:258–261

    Article  CAS  PubMed  Google Scholar 

  71. Toyota M, Ahuja N, Ohe-Toyota M et al (1999) GpG island methylator phenotype in colorectal cancer. Proc Natl Acad Sci U S A 96:8681–8686

    Article  CAS  PubMed  Google Scholar 

  72. Jones PA, Baylin SB (2007) The epigenomics of cancer. Cell 128:683–692

    Article  CAS  PubMed  Google Scholar 

  73. Agalioti T, Cheb G, Thanos D (2002) Deciphering the transcriptional histone acetylation code for a human gene. Cell 111:381–392

    Article  CAS  PubMed  Google Scholar 

  74. Boumber YA, Kondo Y, Chen X (2007) RIL, a LIM gene on 5q31, is silenced by methylation in cancer and sensitizes cancer cells to apoptosis. Cancer Res 67:1997–2005

    Article  CAS  PubMed  Google Scholar 

  75. Quesned B, Guillerm G, Verseecque R et al (1988) Methylation of the P15NK4b gene in myelodysplastic syndromes is frequent and acquired during disease progression. Blood 91:2985–2990

    Google Scholar 

  76. Tien HF, Tang JL, Tsay W (2001) Methylation of the p15NK4b gene in myelodysplastic syndrome it can be detected early at diagnosis or during disease progression and is highly associated with leukemic transformation. Br J Haematol 112:148–154

    Article  CAS  PubMed  Google Scholar 

  77. Jiang Y, Dunbar A, Gondek LP et al (2009) Aberrant DNA methylation is a dominant mechanism in MDS progression to AML. Blood 113:1315–1325

    Article  CAS  PubMed  Google Scholar 

  78. Hofmann WK, Lübert M, Hoelzer D, Koeffer P (2004) Myelodysplastic syndromes. Hematol J 5:1–8

    Article  PubMed  Google Scholar 

  79. Deguchi K, Gilliland DG (2002) Cooperativity between mutations in tyrosine kinases and in hematopoietic transcription factors in AML. Leukemia 16:740–744

    Article  CAS  PubMed  Google Scholar 

  80. Pellagatti A, Cazzola M, Giagounidis A et al (2010) Deregulated gene expression pathways in myelodysplastic syndrome hematopoietic stem cells. Leukemia 24:756–765

    Article  CAS  PubMed  Google Scholar 

  81. Olney JH, Le Beau MM (2001) The cytogenetics of myelodysplastic syndromes. Best Pract Res Clin Haematol 14:479–495

    Article  CAS  PubMed  Google Scholar 

  82. Epling-Burnette PK, List AF (2009) Advancements in the molecular pathogenesis of myelodysplastic syndrome. Curr Opin Hematol 16:70–76

    Article  CAS  PubMed  Google Scholar 

  83. Mohamedali A, Mufti GJ (2008) Van-den Berghe’s 5q- syndrome in 2008. Br J Haematol 144: 157–168

    Article  PubMed  Google Scholar 

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  1. Hematology and Oncology Service, Valencia University Clinic Hospital, Av. Blasco Ibáñez, 17, ES-46010, Valencia, Spain

    Mar Tormo, Isabel Marugán & Marisa Calabuig

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  1. Mar Tormo
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  2. Isabel Marugán
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Correspondence to Mar Tormo.

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Tormo, M., Marugán, I. & Calabuig, M. Myelodysplastic syndromes: an update on molecular pathology. Clin Transl Oncol 12, 652–661 (2010). https://doi.org/10.1007/s12094-010-0574-9

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