International Journal of Hematology

, Volume 73, Issue 4, pp 429–437 | Cite as

Chromosome and Molecular Abnormalities in Myelodysplastic Syndromes

Progress in hematology


Cytogenetic abnormalities are seen in approximately 50% of cases of myelodysplastic syndrome (MDS) and 80% of cases of secondary MDS (following chemotherapy or radiotherapy). These abnormalities generally consist of partial or complete chromosome deletion or addition (del5q, -7, +8, -Y, del20q), whereas balanced or unbalanced translocations are rarely found in MDS. Fluorescence hybridization techniques (fluorescence in situ hybridization [FISH], multiplex FISH, and spectral karyotyping) are useful in detecting chromosomal anomalies in cases in which few mitoses are obtained or rearrangements are complex. Ras mutations are the molecular abnormalities most frequently found in MDS, followed by p15 gene hypermethylation, FLT3 duplications, and p53 mutations, but none of these abnormalities are specific for MDS. The rare cases of balanced translocations in MDS have allowed the identification of genes whose rearrangements appear to play a role in the pathogenesis of some cases of MDS. These genes include MDS1-EVI1 in t(3;3) or t(3;21) translocations, TEL in t(5;12), HIP1 in t(5;7), MLF1 in t(3;5), and MEL1 in t(1;3). Genes more frequently implicated in the pathogenesis of MDS cases, such as those involving del5q, remain unknown, although some candidate genes are currently being studied. Cytogenetic and known molecular abnormalities generally carry a poor prognosis in MDS and can be incorporated into prognostic scoring systems such as the International Prognostic Scoring System.

Key words

Myelodysplastic syndromes Chromosomes Gene rearrangements 


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  1. 1.
    Fenaux P. Myelodysplastic syndromes.Hematol Cell Ther. 1996;38:363–380.CrossRefGoogle Scholar
  2. 2.
    Fenaux P, Morel P, Lai JL. Cytogenetics of myelodysplastic syndromes.Semin Hematol. 1996;33:127–138.Google Scholar
  3. 3.
    Levine EG, Bloomfield CD. Leukemias and myelodysplastic syndromes secondary to drug, radiation, and environmental exposure.Semin Oncol. 1992;19:47–84.Google Scholar
  4. 4.
    Rothman N, Smith MT, Hayes RB, et al. Benzene poisoning, a risk factor for hematological malignancy, is associated with the NQO1 609C→T mutation and rapid fractional excretion of chlorzoxa-zone.Cancer Res. 1997;57:2839–2842.Google Scholar
  5. 5.
    Heim S, Mitelman F. Chromosome abnormalities in the myelodys-plastic syndromes.Clin Haematol. 1986;15:1003–1021.Google Scholar
  6. 6.
    Heim S. Cytogenetic findings in primary and secondary MDS.Leuk Res. 1992;16:43–46.CrossRefGoogle Scholar
  7. 7.
    Knapp RH, Dewald GW, Pierre RV. Cytogenetic studies in 174 consecutive patients with preleukemic or myelodysplastic syndromes.Mayo Clin Proc. 1985;60:507–516.CrossRefGoogle Scholar
  8. 8.
    Morel P, Hebbar M, Lai JL, et al. Cytogenetic analysis has strong independent prognostic value in de novo myelodysplastic syndromes and can be incorporated in a new scoring system: a report on 408 cases.Leukemia. 1993;7:1315–1323.Google Scholar
  9. 9.
    Mufti GJ. Chromosomal deletions in the myelodysplastic syndrome.Leuk Res. 1992;16:35–41.CrossRefGoogle Scholar
  10. 10.
    Musilova J, Michalova K. Chromosome study of 85 patients with myelodysplastic syndrome.Cancer Genet Cytogenet. 1988;33:39–50.CrossRefGoogle Scholar
  11. 11.
    Nowell PC. Chromosome abnormalities in myelodysplastic syndromes.Semin Oncol. 1992;19:25–33.Google Scholar
  12. 12.
    Toyama K, Ohyashiki K, Yoshida Y, et al. Clinical implications of chromosomal abnormalities in 401 patients with myelodysplastic syndromes: a multicentric study in Japan.Leukemia. 1993;7:499–508.Google Scholar
  13. 13.
    Weh HJ, Calavrezos A, Seeger D, Kuse R, Hossfeld DK. Cytogenetic studies in 69 patients with myelodysplastic syndromes (MDS).Eur J Haematol. 1987;38:166–172.CrossRefGoogle Scholar
  14. 14.
    Flactif M, Lai JL, Preudhomme C, Fenaux P. Fluorescence in situ hybridization improves the detection of monosomy 7 in myelodys-plastic syndromes.Leukemia. 1994;8:1012–1018.Google Scholar
  15. 15.
    Jenkins RB, Le Beau MM, Kraker WJ, et al. Fluorescence in situ hybridization: a sensitive method for trisomy 8 detection in bone marrow specimens.Blood. 1992;79:3307–3315.Google Scholar
  16. 16.
    Kakazu N, Taniwaki M, Horiike S, et al. Combined spectral kary-otyping and DAPI banding analysis of chromosome abnormalities in myelodysplastic syndrome.Genes Chromosomes Cancer. 1999;26:336–345.CrossRefGoogle Scholar
  17. 17.
    Mohr B, Bornhauser M, Thiede C, et al. Comparison of spectral karyotyping and conventional cytogenetics in 39 patients with acute myeloid leukemia and myelodysplastic syndrome.Leukemia. 2000;14:1031–1038.CrossRefGoogle Scholar
  18. 18.
    Soenen V, Fenaux P, Flactif M, et al. Combined immunophenotyping and in situ hybridization (FICTION): a rapid method to study cell lineage involvement in myelodysplastic syndromes.Br J Haematol. 1995;90:701–706.CrossRefGoogle Scholar
  19. 19.
    Lessard M, Herry A, Berthou C, et al. FISH investigation of 5q and 7q deletions in MDS/AML reveals hidden translocations, insertions and fragmentations of the same chromosomes.Leuk Res. 1998;22:303–312.CrossRefGoogle Scholar
  20. 20.
    Greenberg P, Cox C, LeBeau MM, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes.Blood. 1997;89:2079–2088.PubMedGoogle Scholar
  21. 21.
    Sole F, Espinet B, Sanz GF, et al. Incidence, characterization and prognostic significance of chromosomal abnormalities in 640 patients with primary myelodysplastic syndromes. Grupo Cooper-ativo Espanol de Citogenetica Hematologica.Br J Haematol. 2000;108:346–356.CrossRefGoogle Scholar
  22. 22.
    West RR, Stafford DA, White AD, Bowen DT, Padua RA. Cytogenetic abnormalities in the myelodysplastic syndromes and occupational or environmental exposure.Blood. 2000;95:2093–2097.Google Scholar
  23. 23.
    Stillman WS, Varella-Garcia M, Irons RD. The benzene metabolites hydroquinone and catechol act in synergy to induce dose-dependent hypoploidy and -5q31 in a human cell line.Leuk Lymphoma. 1999;35:269–281.CrossRefGoogle Scholar
  24. 24.
    Stillman WS, Varella-Garcia M, Irons RD. The benzene metabolite, hydroquinone, selectively induces 5q31-and -7 in human CD34+CD19- bone marrow cells.Exp Hematol. 2000;28:169–176.CrossRefGoogle Scholar
  25. 25.
    Andersen MK, Pedersen-Bjergaard J. Increased frequency of dicentric chromosomes in therapy-related MDS and AML compared to de novo disease is significantly related to previous treatment with alkylating agents and suggests a specific susceptibility to chromosome breakage at the centromere.Leukemia. 2000;14:105–111.CrossRefGoogle Scholar
  26. 26.
    Davico L, Sacerdote C, Ciccone G, et al. Chromosome 8, occupational exposures, smoking, and acute nonlymphocytic leukemias: a population-based study.Cancer Epidemiol Biomarkers Prev. 1998;7:1123–1125.Google Scholar
  27. 27.
    Nisse C, Lorthois C, Dorp V, Eloy E, Haguenoer JM, Fenaux P. Exposure to occupational and environmental factors in myelodys-plastic syndromes. Preliminary results of a case-control study.Leukemia. 1995;9:693–699.Google Scholar
  28. 28.
    Abruzzese E, Radford JE, Miller JS, et al. Detection of abnormal pretransplant clones in progenitor cells of patients who developed myelodysplasia after autologous transplantation.Blood. 1999;94:1814–1819.Google Scholar
  29. 29.
    Gundestrup M, Klarskov Andersen M, Sveinbjornsdottir E, Rafns-son V, Storm HH, Pedersen-Bjergaard J. Cytogenetics of myelodys-plasia and acute myeloid leukaemia in aircrew and people treated with radiotherapy.Lancet. 2000;356:2158.CrossRefGoogle Scholar
  30. 30.
    Paquette RL, Landaw EM, Pierre RV, et al. N-ras mutations are associated with poor prognosis and increased risk of leukemia in myelodysplastic syndrome.Blood. 1993;82:590–599.Google Scholar
  31. 31.
    Shannon KM, O’Connell P, Martin GA, et al. Loss of the normal NF1 allele from the bone marrow of children with type 1 neurofi-bromatosis and malignant myeloid disorders.N Engl J Med. 1994;330:597–601.CrossRefGoogle Scholar
  32. 32.
    Side L, Taylor B, Cayouette M, et al. Homozygous inactivation of the NF1 gene in bone marrow cells from children with neurofibro-matosis type 1 and malignant myeloid disorders.N Engl J Med. 1997;336:1713–1720.CrossRefGoogle Scholar
  33. 33.
    Side LE, Emanuel PD, Taylor B, et al. Mutations of the NF1 gene in children with juvenile myelomonocytic leukemia without clinical evidence of neurofibromatosis, type 1.Blood. 1998;92:267–272.Google Scholar
  34. 34.
    Largaespada DA, Brannan CI, Jenkins NA, Copeland NG. Nf1 deficiency causes Ras-mediated granulocyte/macrophage colony stimulating factor hypersensitivity and chronic myeloid leukaemia.Nat Genet. 1996;12:137–143.CrossRefGoogle Scholar
  35. 35.
    Preudhomme C, Vachee A, Quesnel B, Wattel E, Cosson A, Fenaux P. Rare occurrence of mutations of the FLR exon of the neurofi-bromatosis 1 (NF1) gene in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML).Leukemia. 1993;7:1071.PubMedGoogle Scholar
  36. 36.
    Jonveaux P, Fenaux P, Quiquandon I, et al. Mutations in the p53 gene in myelodysplastic syndromes.Oncogene. 1991;6:2243–2247.PubMedGoogle Scholar
  37. 37.
    Lai JL, Preudhomme C, Zandecki M, et al. Myelodysplastic syndromes and acute myeloid leukemia with 17p deletion. An entity characterized by specific dysgranulopoiesis and a high incidence of P53 mutations.Leukemia. 1995;9:370–381.PubMedGoogle Scholar
  38. 38.
    Soenen V, Preudhomme C, Roumier C, Daudignon A, Lai JL, Fenaux P. 17p Deletion in acute myeloid leukemia and myelodys-plastic syndrome. Analysis of breakpoints and deleted segments by fluorescence in situ.Blood. 1998;91:1008–1015.PubMedGoogle Scholar
  39. 39.
    Sterkers Y, Preudhomme C, Lai JL, et al. Acute myeloid leukemia and myelodysplastic syndromes following essential thrombo-cythemia treated with hydroxyurea: high proportion of cases with 17p deletion.Blood. 1998;91:616–622.PubMedGoogle Scholar
  40. 40.
    Quesnel B, Preudhomme C, Philippe N, et al. p16 gene homozygous deletions in acute lymphoblastic leukemia.Blood. 1995;85:657–663.Google Scholar
  41. 41.
    Quesnel B, Guillerm G, Vereecque R, et al. Methylation of the p15(INK4b) gene in myelodysplastic syndromes is frequent and acquired during disease progression.Blood. 1998;91:2985–2990.Google Scholar
  42. 42.
    Tien HF, Tang JH, Tsay W, et al. Methylation of the p15(INK4B) gene in myelodysplastic syndrome: it can be detected early at diagnosis or during disease progression and is highly associated with leukaemic transformation.Br J Haematol. 2001;112:148–154.CrossRefGoogle Scholar
  43. 43.
    Preudhomme C, Vachee A, Lepelley P, et al. Inactivation of the retinoblastoma gene appears to be very uncommon in myelodys-plastic syndromes.Br J Haematol. 1994;87:61–67.CrossRefGoogle Scholar
  44. 44.
    Golub TR, Barker GF, Lovett M, Gilliland DG. Fusion of PDGF receptor beta to a novel ets-like gene, tel, in chronic myelomono-cytic leukemia with t(5;12) chromosomal translocation.Cell. 1994;77:307–316.CrossRefGoogle Scholar
  45. 45.
    Streubel B, Sauerland C, Heil G, et al. Correlation of cytogenetic, molecular cytogenetic, and clinical findings in 59 patients with ANLL or MDS and abnormalities of the short arm of chromosome 12.Br J Haematol. 1998;100:521–533.CrossRefGoogle Scholar
  46. 46.
    Nucifora G, Rowley JD. AML1 and the 8;21 and 3;21 translocations in acute and chronic myeloid leukemia.Blood. 1995;86:1–14.Google Scholar
  47. 47.
    Soderholm J, Kobayashi H, Mathieu C, Rowley JD, Nucifora G. The leukemia-associated gene MDS1/EVI1 is a new type of GATA-binding transactivator.Leukemia. 1997;11:352–358.CrossRefGoogle Scholar
  48. 48.
    Sood R, Talwar-Trikha A, Chakrabarti SR, Nucifora G. MDS1/EVI1 enhances TGF-beta1 signaling and strengthens its growth-inhibitory effect but the leukemia-associated fusion protein AML1/MDS1/EVI1, product of the t(3;21), abrogates growth-inhibition in response to TGF-beta1.Leukemia. 1999;13:348–357.CrossRefGoogle Scholar
  49. 49.
    Sitailo S, Sood R, Barton K, Nucifora G. Forced expression of the leukemia-associated gene EVI1 in ES cells: a model for myeloid leukemia with 3q26 rearrangements.Leukemia. 1999;13:1639–1645.CrossRefGoogle Scholar
  50. 50.
    Nishiyama M, Arai Y, Tsunematsu Y, et al. 11p15 translocations involving the NUP98 gene in childhood therapy-related acute myeloid leukemia/myelodysplastic syndrome.Genes Chromosomes Cancer. 1999;26:215–220.CrossRefGoogle Scholar
  51. 51.
    Ahuja HG, Felix CA, Aplan PD. The t(11;20)(p15;q11) chromosomal translocation associated with therapy-related myelodysplastic syndrome results in an NUP98-TOP1 fusion.Blood. 1999;94:3258–3261.Google Scholar
  52. 52.
    Mochizuki N, Shimizu S, Nagasawa T, et al. A novel gene, MEL1, mapped to 1p36.3 is highly homologous to the MDS1/EVI1 gene and is transcriptionally activated in t(1;3)(p36;q21)-positive leukemia cells.Blood. 2000;96:3209–3214.Google Scholar
  53. 53.
    Yoneda-Kato N, Look AT, Kirstein MN, et al. The t(3;5)(q25.1;q34)of myelodysplastic syndrome and acute myeloid leukemia produces a novel fusion gene, NPM-MLF1.Oncogene. 1996;12:265–275.Google Scholar
  54. 54.
    Matsumoto N, Yoneda-Kato N, Iguchi T, et al. Elevated MLF1 expression correlates with malignant progression from myelodys-plastic syndrome.Leukemia. 2000;14:1757–1765.CrossRefGoogle Scholar
  55. 55.
    Ross TS, Bernard OA, Berger R, Gilliland DG. Fusion of Hunt-ingtin interacting protein 1 to platelet-derived growth factor beta receptor (PDGFbetaR) in chronic myelomonocytic leukemia with t(5;7)(q33;q11.2).Blood. 1998;91:4419–4426.Google Scholar
  56. 56.
    Ridge SA, Worwood M, Oscier D, Jacobs A, Padua RA. FMS mutations in myelodysplastic, leukemic, and normal subjects.Proc Natl Acad Sci U S A. 1990;87:1377–1380.CrossRefPubMedGoogle Scholar
  57. 57.
    Horiike S, Yokota S, Nakao M, et al. Tandem duplications of the FLT3 receptor gene are associated with leukemic transformation of myelodysplasia.Leukemia. 1997;11:1442–1446.CrossRefGoogle Scholar
  58. 58.
    Tamaki H, Ogawa H, Ohyashiki K, et al. The Wilms’ tumor gene WT1 is a good marker for diagnosis of disease progression of myelodysplastic syndromes.Leukemia. 1999;13:393–399.CrossRefPubMedGoogle Scholar
  59. 59.
    Imai Y, Kurokawa M, Izutsu K, et al. Mutations of the AML1 gene in myelodysplastic syndrome and their functional implications in leukemogenesis.Blood. 2000;96:3154–3160.Google Scholar
  60. 60.
    Harris NL, Jaffe ES, Diebold J, et al. World Health Organization classification of neoplastic diseases of the hematopoietic and lym-phoid tissues: report of the Clinical Advisory Committee meeting—Airlie House,Virginia, November 1997.J Clin Oncol. 1999;17:3835–3849.CrossRefGoogle Scholar
  61. 61.
    Boultwood J, Lewis S, Wainscoat JS. The 5q- syndrome.Blood. 1994;84:3253–3260.Google Scholar
  62. 62.
    Pedersen B, Jensen IM. Clinical and prognostic implications of chromosome 5q deletions: 96 high resolution studied patients.Leukemia. 1991;5:566–573.Google Scholar
  63. 63.
    Xie H, Hu Z, Chyna B, Horrigan SK, Westbrook CA. Human mortalin (HSPA9): a candidate for the myeloid leukemia tumor suppressor gene on 5q31.Leukemia. 2000;14:2128–2134.CrossRefGoogle Scholar
  64. 64.
    Jaju RJ, Boultwood J, Oliver FJ, et al. Molecular cytogenetic delineation of the critical deleted region in the 5q- syndrome.Genes Chromosomes Cancer. 1998;22:251–256.CrossRefGoogle Scholar
  65. 65.
    Boultwood J, Fidler C, Strickson AJ, et al. Transcription mapping of the 5q- syndrome critical region: cloning of two novel genes and sequencing, expression, and mapping of a further six novel cDNAs.Genomics. 2000;66:26–34.CrossRefGoogle Scholar
  66. 66.
    Fairman J, Wang RY, Liang H, et al. Translocations and deletions of 5q13.1 in myelodysplasia and acute myelogenous leukemia: evidence for a novel critical locus.Blood. 1996;88:2259–2266.Google Scholar
  67. 67.
    Horrigan SK, Westbrook CA, Kim AH, Banerjee M, Stock W, Larson RA. Polymerase chain reaction-based diagnosis of del (5q) in acute myeloid leukemia and myelodysplastic syndrome identifies a minimal deletion interval.Blood. 1996;88:2665–2670.Google Scholar
  68. 68.
    Roulston D, Espinosa R III, Stoffel M, Bell GI, Le Beau MM. Molecular genetics of myeloid leukemia: identification of the commonly deleted segment of chromosome 20.Blood. 1993;82:3424–3429.Google Scholar
  69. 69.
    Kiuru-Kuhlefelt S, Kristo P, Ruutu T, Knuutila S, Kere J. Evidence for two molecular steps in the pathogenesis of myeloid disorders associated with deletion of chromosome 7 long arm.Leukemia. 1997;11:2097–2104.CrossRefGoogle Scholar
  70. 70.
    McClure RF, Dewald GW, Hoyer JD, Hanson CA. Isolated isochromosome 17q: a distinct type of mixed myeloproliferative disorder/myelodysplastic syndrome with an aggressive clinical course.Br J Haematol. 1999;106:445–454.CrossRefGoogle Scholar
  71. 71.
    Preudhomme C, Nisse C, Hebbar M, et al. Glutathione S trans-ferase theta 1 gene defects in myelodysplastic syndromes and their correlation with karyotype and exposure to potential carcinogens.Leukemia. 1997;11:1580–1582.CrossRefGoogle Scholar
  72. 72.
    Sasai Y, Horiike S, Misawa S, et al. Genotype of glutathione S-transferase and other genetic configurations in myelodysplasia.Leuk Res. 1999;23:975–981.CrossRefGoogle Scholar
  73. 73.
    Gattermann N. From sideroblastic anemia to the role of mitochon-drial DNA mutations in myelodysplastic syndromes.Leuk Res. 2000;24:141–151.CrossRefGoogle Scholar
  74. 74.
    Ohyashiki JH, Iwama H, Yahata N, et al. Telomere stability is frequently impaired in high-risk groups of patients with myelodys-plastic syndromes.Clin Cancer Res. 1999;5:1155–1160.Google Scholar
  75. 75.
    Boultwood J, Fidler C, Kusec R, et al. Telomere length in myelodys-plastic syndromes.Am J Hematol. 1997;56:266–271.CrossRefGoogle Scholar
  76. 76.
    Wattel E, Preudhomme C, Hecquet B, et al. p53 mutations are associated with resistance to chemotherapy and short survival in hematologic malignancies.Blood. 1994;84:3148–3157.Google Scholar

Copyright information

© The Japanese Society of Hematology 2001

Authors and Affiliations

  1. 1.CHU de LilleFrance

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