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International Journal of Hematology

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

Chromosome and Molecular Abnormalities in Myelodysplastic Syndromes

  • Pierre Fenaux
Progress in hematology

Abstract

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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References

  1. 1.
    Fenaux P. Myelodysplastic syndromes.Hematol Cell Ther. 1996;38:363–380.CrossRefPubMedGoogle Scholar
  2. 2.
    Fenaux P, Morel P, Lai JL. Cytogenetics of myelodysplastic syndromes.Semin Hematol. 1996;33:127–138.PubMedGoogle Scholar
  3. 3.
    Levine EG, Bloomfield CD. Leukemias and myelodysplastic syndromes secondary to drug, radiation, and environmental exposure.Semin Oncol. 1992;19:47–84.PubMedGoogle 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.PubMedGoogle Scholar
  5. 5.
    Heim S, Mitelman F. Chromosome abnormalities in the myelodys-plastic syndromes.Clin Haematol. 1986;15:1003–1021.PubMedGoogle Scholar
  6. 6.
    Heim S. Cytogenetic findings in primary and secondary MDS.Leuk Res. 1992;16:43–46.CrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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.PubMedGoogle Scholar
  9. 9.
    Mufti GJ. Chromosomal deletions in the myelodysplastic syndrome.Leuk Res. 1992;16:35–41.CrossRefPubMedGoogle Scholar
  10. 10.
    Musilova J, Michalova K. Chromosome study of 85 patients with myelodysplastic syndrome.Cancer Genet Cytogenet. 1988;33:39–50.CrossRefPubMedGoogle Scholar
  11. 11.
    Nowell PC. Chromosome abnormalities in myelodysplastic syndromes.Semin Oncol. 1992;19:25–33.PubMedGoogle 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.PubMedGoogle 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.CrossRefPubMedGoogle 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.PubMedGoogle 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.PubMedGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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.PubMedGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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.PubMedGoogle 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.PubMedGoogle 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.PubMedGoogle 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.CrossRefPubMedGoogle 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.PubMedGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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.PubMedGoogle 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.CrossRefPubMedGoogle 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.PubMedGoogle 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.PubMedGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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.PubMedGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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.PubMedGoogle 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.PubMedGoogle 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.PubMedGoogle 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.CrossRefPubMedGoogle 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.PubMedGoogle 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.CrossRefPubMedPubMedCentralGoogle 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.CrossRefPubMedGoogle 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.PubMedGoogle 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.CrossRefPubMedGoogle Scholar
  61. 61.
    Boultwood J, Lewis S, Wainscoat JS. The 5q- syndrome.Blood. 1994;84:3253–3260.PubMedGoogle 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.PubMedGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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.PubMedGoogle 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.PubMedGoogle 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.PubMedGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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.PubMedGoogle Scholar
  75. 75.
    Boultwood J, Fidler C, Kusec R, et al. Telomere length in myelodys-plastic syndromes.Am J Hematol. 1997;56:266–271.CrossRefPubMedGoogle 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.PubMedGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2001

Authors and Affiliations

  1. 1.CHU de LilleFrance

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