Skip to main content
SpringerLink
Log in

Molecular pathogenesis of MDS

  • Myelodysplastic Syndrome
  • Published:
International Journal of Hematology Aims and scope Submit manuscript

Abstract

Myelodysplastic syndromes (MDS) are considered to be a family of clonal disorders of hematopoietic stem cells that are characterized by ineffective hematopoiesis and susceptibility to acute myelogenous leukemias, and are shown to be strikingly refractory to current therapeutic modalities. A substantial proportion of these complex diseases arise in the setting of exposures to environmental or occupational toxins, including cytotoxic therapy for a prior malignancy or other disorder. The conversion of a normal stem cell into a preleukemic and ultimately leukemic state is a multistep process requiring the accumulation of a number of genetic lesions. On the genomic level, MDS is typified by losses and translocations involving certain key gene segments, with disruption of the normal structure and function of genes that control the balance of proliferation and differentiation of hematopoietic precursors. More than a half of the chromosomal abnormalities in MDS comprise deletions of chromosomes 5, 7, 11, 12, 13 and 20. This evidence suggests that as yet unidentified tumor suppressor genes should have important roles in the molecular mechanisms of MDS. Further molecular approaches to such genetic lesions will identify the relevant tumor suppressor genes. over the past years, major signal transduction molecules were identified and their genetic alterations molecules, cell cycle regulators, and transcription factors. Among them, notable is transcription factors that regulate both proliferation and differentiation of hematopoitic stem cells. The disruption of the normal flow of the signal transduction pathways involving these molecules translates into ineffective multilineage hematopoiesis and bone marrow failure. Therefore, MDS provides a fertile testing ground on which we could study the molecular dissection implicated in the multistep leukemogenesis.

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

  1. Gersuk GM, Beckham C, Loken MR, et al. A role for tumour necrosis factor-alpha, Fas and Fas-Ligand in marrow failure associated with myelodysplastic syndrome.Br J Haematol. 1998;103:176–188.

    Article  PubMed  CAS  Google Scholar 

  2. Raza A, Gezer S, Mundle S, et al. Apoptosis in bone marrow biopsy samples involving stromal and hematopoietic cells in 50 patients with myelodysplastic syndromes.Blood. 1995;86: 268–276.

    PubMed  CAS  Google Scholar 

  3. Shetty V, Mundle S, Alvi S, et al. Measurement of apoptosis, proliferation and three cytokines in 46 patients with myelodysplastic syndromes.Leuk Res. 1996;20:891–900.

    Article  PubMed  CAS  Google Scholar 

  4. Haase D, Feuring-Buske M, Schafer C, et al. Cytogenetic analysis of CD34+ subpopulations in AML and MDS characterized by the expression of CD38 and CD117.Leukemia. 1997;11:674–679.

    Article  PubMed  CAS  Google Scholar 

  5. Loeb LA. Caneer cells exhibit a mutator phenotype.Adv Cancer Res. 1998;72:25–56.

    Article  PubMed  CAS  Google Scholar 

  6. Arzimanoglou II, Gilbert F, Barber HR. Microsatellite instability in human solid tumors.Cancer. 1998;82:1808–1820.

    Article  PubMed  CAS  Google Scholar 

  7. Third MIC Cooperative Group Study. Recommendations for a morphologic, immunologic, and cytogenetic (MIC) working classification of the primary and therapy-related myelodysplastic disorders.Cancer Genet Cytogenet. 1988;32:1–10.

    Article  Google Scholar 

  8. Mecucci C. Molecular features of primary MDS with cytogenetic changes.Leuk Res. 1998;22:293–302.

    Article  PubMed  CAS  Google Scholar 

  9. Van den Berghe H, Vermaelen K, Mecucci C, Barbieri D, Tricot G. The 5q-anomaly.Cancer Genet Cytogenet. 1985;17: 189–255.

    Article  PubMed  Google Scholar 

  10. Boultwood J, Lewis S, Wainscoat JS. The 5q-syndrome.Blood. 1994;84:3253–3260.

    PubMed  CAS  Google Scholar 

  11. Boultwood J, Rack K, Kelly S, et al. Loss of both CSF1R (FMS) alleles in patients with myelodysplasia and a chromosome 5 deletion.Proc Natl Acad Sci USA. 1991;88:6176–6180.

    Article  PubMed  CAS  Google Scholar 

  12. Willman CL, Sever CE, Pallavicini MG, et al. Deletion of IRF-1, mapping to chromosome 5q31.1, in human leukemia and preleukemic myelodysplasia.Science. 1993;259:968–971.

    Article  PubMed  CAS  Google Scholar 

  13. Lezon-Geyda K, Najfeld V, Johnson EM. Deletions of PURA, at 5q31, and PURB, at 7p13, in myelodysplastic syndrome and progression to acute myelogenous leukemia.Leukemia. 2001;15:954–962.

    Article  PubMed  CAS  Google Scholar 

  14. 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.

    PubMed  CAS  Google Scholar 

  15. Borkhardt A, Bojesen S, Haas OA, et al. The human GRAF gene is fused to MLL in a unique t(5;11) (q31;q23) and both alleles are disrupted in three cases of myelodysplastic syndrome/acute myeloid leukemia with a deletion 5q.Proc Natl Acad Sci USA. 2000;97:9168–9173.

    Article  PubMed  CAS  Google Scholar 

  16. Yagasaki F, Jinnai I, Yoshida S, et al. fusion of TEL/ ETV6 to a novel ACS2 in myelodysplastic syndrome and acute myelogenous leukemia with t(5;12)(q31;p13).Genes Chromosomes Cancer. 1999;26:192–202.

    Article  PubMed  CAS  Google Scholar 

  17. Jaju RJ, Fidler C, Haas OA, et al. A novel gene, NSD1, is fused to NUP98 in the t(5;11)(q35;p15.5) inde novo childhood acute myeloid leukemia.Blood. 2001;98:1264–1267.

    Article  PubMed  CAS  Google Scholar 

  18. Johnson EJ, Scherer SW, Osborne L, et al. Molecular definition of a narrow interval at 7q22.1 associated with myelodysplasia.Blood. 1996;87:3579–3586.

    PubMed  CAS  Google Scholar 

  19. Kratz CP, Emerling BM, Bonifas J, et al. Genomic structure of the PIK3CG gene on chromosome band 7q22 and evaluation as a candidate myeloid tumor suppressor.Blood. 2002;99:372–374.

    Article  PubMed  CAS  Google Scholar 

  20. Side L, Taylor B, Cayouette M, et al. Homozygous inactivation of the NF1 gene in bone marrow cells from children with neurofibromatosis type 1 and malignant myeloid disorders.New Engl J Med. 1997;336:1713–1720.

    Article  PubMed  CAS  Google Scholar 

  21. Stephenson J, Lizhen H, Mufti GJ. Possible co-existence of RAS activation and monosomy 7 in the leukaemic transformation of myelodysplastic syndromes.Leuk Res. 1995;19:741–748.

    Article  PubMed  CAS  Google Scholar 

  22. Luna-Fineman S, Shannon KM, Lange BJ. Childhood monosomy 7: epidemiology, biology, and mechanistic implications.Blood. 1995;85:1985–1999.

    PubMed  CAS  Google Scholar 

  23. Asimakopoulos FA, Holloway TL, Nacheva EP, Scott MA, Fenaux P, Green AR. Detection of chromosome 20q deletions in bone marrow metaphases but not peripheral blood granulocytes in patients with myeloproliferative disorders or myelodysplastic syndromes.Blood. 1996;87:1561–1570.

    PubMed  CAS  Google Scholar 

  24. Asimakopoulos FA, Green AR. Deletions of chromosome 20q and the pathogenesis of myeloproliferative disorders.Br J Haematol. 1996;95:219–226.

    Article  PubMed  CAS  Google Scholar 

  25. la Starza R, Wlodarska I, Aventin A, et al. Molecular delineation of 13q deletion boundaries in 20 patients with myeloid malignancies.Blood. 1998;91:231–237.

    PubMed  Google Scholar 

  26. Mecucci C, Van Orshoven A, Vermaelen K, et al. 11q-chromosome is associated with abnormal iron stores in myelodysplastic syndromes [Journal Article].Cancer Genet Cytogenet. 1987;27:39–44.

    Article  PubMed  CAS  Google Scholar 

  27. Hoglund M, Johansson B, Pedersen-Bjergaard J, Marynen P, Mitelman F. Molecular characterization of 12p abnormalities in hematologic malignancies: deletion of KIP1, rearrangement of TEL, and amplification of CCND2.Blood. 1996;87:324–330.

    PubMed  CAS  Google Scholar 

  28. Golub TR, Barker GF, Lovett M, Gilliland DG. Fusion of PDGF receptor beta to a novel ets-like gene, tel, in chronic myelomonocytic leukemia with t(5;12) chromosomal translocation.Cell. 1994;77:307–316.

    Article  PubMed  CAS  Google Scholar 

  29. Wlodarska I, Mecucci C, Marynen P, et al. TEL gene is involved in myelodysplastic syndromes with either the typical t(5;12)(q33;p13) translocation or its variant t(10;12)(q24;p13).Blood. 1995;85:2848–2852.

    PubMed  CAS  Google Scholar 

  30. Carroll M, Tomasson MH, Barker GF, Golub TR, Gilliland DG. The TEL/platelet-derived growth factor beta receptor (PDGF beta R) fusion in chronic myelomonocytic leukemia is a transforming protein that self-associates and activates PDGF beta R kinase-dependent signaling pathways.Proc Natl Acad Sci USA. 1995;93:14845–1450.

    Article  Google Scholar 

  31. Salomon-Nguyen F, Della-Valle V, Mauchauffe M, et al. The t(1;12) (q21;p13) translocation of human acute myelobiastic leukemia results in a TEL-ARNT fusion.Proc Natl Acad Sci USA. 2000;97:6757–6762.

    Article  PubMed  CAS  Google Scholar 

  32. Buijs A, Sherr S, van Baal S, et al. Translocation (12;22) (p13;q11) in myeloproliferative disorders results in fusion of the ETS-like TEL gene on 12p13 to the MN1 gene on 22q11.Oncogene. 1995;10:1511–1519.

    PubMed  CAS  Google Scholar 

  33. Raynaud SD, Baens M, Grosgeorge J, et al. Fluorescence in situ hybridization analysis of t(3;12)(q26;p13): a recurring chromosomal abnormality involving the TEL gene (ETV6) in myelodysplastic syndromes.Blood. 1996;88:682–689.

    PubMed  CAS  Google Scholar 

  34. Yagasaki F, Jinnai I, Yoshida S, et al. Fusion of TEL/ETV6 to a novel ACS2 in myelodysplastic syndrome and acute myelogenous leukemia with t(5;12)(q31;p13).Genes Chromosomes Cancer. 1999;26:192–202.

    Article  PubMed  CAS  Google Scholar 

  35. Ayton PM, Cleary ML. Molecular mechanism of leukemogenesismediated by MLL fusion proteins.Oncogene. 2001;20: 5695–5707.

    Article  PubMed  CAS  Google Scholar 

  36. Mitani K, Kanda Y, Ogawa S, et al. Cloning of several species of MLL/MEN chimeric cDNAs in myeloid leukemia with t(11;19)(q23;p13.1) translocation.Blood. 1995;85:2017–2024.

    PubMed  CAS  Google Scholar 

  37. Taki T, Sako M, Tsuchida M, Hayashi Y. The t(11;16) (q23;p13) translocation in myelodysplastic syndrome fuses the MLL gene to the CBP gene.Blood. 1997;89:3945–3950.

    PubMed  CAS  Google Scholar 

  38. Caligiuri MA, Strout MP, Schichman SA, et al. Partial tandem duplication of ALL1 as a recurrent molecular defect in acute myeloid leukemia with trisomy 11.Cancer Res. 1996;56: 1418–1425.

    PubMed  CAS  Google Scholar 

  39. Radu A, Blobel G, Moore MS. Identification of a protein complex that is required for nuclear protein import and mediates docking of import substrate to distinct nucleoporins.Proc Natl Acad Sci USA. 1995;92:1769–1773.

    Article  PubMed  CAS  Google Scholar 

  40. Nakamura T, Largaespada DA, Lee MP, et al. Fusion of the nucleoporin gene NUP98 to HOXA9 by the chromosome translocation t(7;11)(p15;p15) in human myeloid leukaemia.Nature Genetics. 1996;12:154–158.

    Article  PubMed  CAS  Google Scholar 

  41. Raza-Egilmez SZ, Jani-Sait SN, Grossi M, Higgins MJ, Shows TB, Aplan PD. NUP98-HOXD13 gene fusion in therapy-related acute myelogenous leukemia.Cancer Res. 1998;58:4269–4273.

    PubMed  CAS  Google Scholar 

  42. 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.

    Article  PubMed  CAS  Google Scholar 

  43. 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.

    PubMed  CAS  Google Scholar 

  44. Arai Y, Hosoda F, Kobayashi H, et al. The inv(11)(p15q22) chromosome translocation of de novo and therapy-related myeloid malignancies results in fusion of the nucleoporin gene, NUP98, with the putative RNA helicase gene, DDX10.Blood. 1997;89:3936–3944.

    PubMed  CAS  Google Scholar 

  45. Soekarman D, von Lindern M, Daenen S, et al. The translocation (6;9)(p23;q34) shows consistent rearrangement of two genes and defines a myeloproliferative disorder with specific clinical features.Blood. 1992;79:2990–2997.

    PubMed  CAS  Google Scholar 

  46. Boer J, Bonten-Surtel J, Grosveld G. Overexpression of the nucleoporin CAN/NUP214 induces growth arrest, nucleocyto-plasmic transport defects, and apoptosis.Mol Cell Biol. 1998; 18:1236–1247.

    PubMed  CAS  Google Scholar 

  47. Jotterand Bellomo M, Parlier V, Muhlematter D, Grob JP, Beris P. Three new cases of chromosome 3 rearrangement in bands q21 and q25 with abnormal thrombopoiesis bring further evidence to the existence of a 3q21q26 syndrome.Cancer Genet Cytogenet. 1992;59:138–160.

    Article  Google Scholar 

  48. Suzukawa K, Parganas E, Gajjar A, et al. Identification of a breakpoint cluster region 3′ of the ribophorin I gene at 3q21 associated with the transcriptional activation of the EVI1 gene in acute myelogenous leukemias with inv(3)(q21q26).Blood. 1994;84:2681–2688.

    PubMed  CAS  Google Scholar 

  49. 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.

    PubMed  CAS  Google Scholar 

  50. Mitani K, Ogawa S, Tanaka T, et al. Generation of the AML1-EVI-1 fusion gene in the t(3;21)(q26;q22) causes blastic crisis in chronic myelocytic leukemia.EMBO Journal. 1994; 13:504–510.

    PubMed  CAS  Google Scholar 

  51. Kurokawa M, Mitani K, Irie K, et al. The oncoprotein Evi-1 represses TGF-beta signalling by inhibiting Smad3.Nature. 1998;394:92–96.

    Article  PubMed  CAS  Google Scholar 

  52. Izutsu K, Kurokawa M, Imai Y, Maki K, Mitani K, Hirai H. The corepressor CtBP interacts with Evi-1 to repress transforming growth factor beta signaling.Blood. 2001;97:2815–2822.

    Article  PubMed  CAS  Google Scholar 

  53. Marshall MS. Ras target proteins in eukaryotic cells.FASEB Journal. 1995;9:1311–1318.

    PubMed  CAS  Google Scholar 

  54. Hirai H, Kobayashi Y, Mano H, et al. A point mutation at codon 13 of the N-ras oncogene in myelodysplastic syndrome.Nature. 1987;327:430–432.

    Article  PubMed  CAS  Google Scholar 

  55. 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.

    PubMed  CAS  Google Scholar 

  56. Hirai H, Okada M, Mizoguchi H, et al. Relationship between an activated N-ras oncogene and chromosomal abnormality during leukemic progression from myelodysplastic syndrome.Blood. 1988;71:256–258.

    PubMed  CAS  Google Scholar 

  57. Yokota S, Kiyoi H, Nakao M, et al. Internal tandem duplication of the FLT3 gene is preferentially seen in acute myeloid leukemia and myelodysplastic syndrome among various hematological malignancies. A study on a large series of patients and cell lines.Leukemia. 1997;11:1605–1609.

    Article  PubMed  CAS  Google Scholar 

  58. 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.

    Article  PubMed  CAS  Google Scholar 

  59. Sugimoto K, Hirano N, Toyoshima H, et al. Mutations of the p53 gene in myelodysplastic syndrome (MDS) and MDS-derived leukemia.Blood. 1993;81:3022–3026.

    PubMed  CAS  Google Scholar 

  60. Song WJ, Sullivan MG, Legare RD, et al. Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia.Nat Genet. 1999; 23:166–175.

    Article  PubMed  CAS  Google Scholar 

  61. Osato M, Asou N, Abdalla E, et al. Biallelic and heterozygous point mutations in the runt domain of the AML1/PEBP2alphaB gene associated with myeloblastic leukemias.Blood. 1999;93:1817–1824.

    PubMed  CAS  Google Scholar 

  62. Preudhomme C, Warot-Loze D, Roumier C, et al. High incidence of biallelic point mutations in the Runt domain of the AML1/PEBP2 alpha B gene in Mo acute myeloid leukemia and in myeloid malignancies with acquired trisomy 21.Blood. 2000;96:2862–2869.

    PubMed  CAS  Google Scholar 

  63. 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.

    PubMed  CAS  Google Scholar 

  64. Pabst T, Mueller BU, Zhang P, et al. Dominant- negative mutations of CEBPA, encoding CCAAT/enhancer binding protein-alpha (C/EBPalpha), in acute myeloid leukemia.Nat Genet. 2001;27:263–270.

    Article  PubMed  CAS  Google Scholar 

  65. Gombart AF, Hofmann WK, Kawano S, et al. Mutations in the gene encoding the transcription factor CCAAT/enhancer binding protein alpha in myelodysplastic syndromes and acute myeloid leukemias.Blood. 2002;99:1332–1340.

    Article  PubMed  CAS  Google Scholar 

  66. Kamb A, Gruis NA, Weaver-Feldhaus J, et al. A cell cycle regulator potentially involved in genesis of many tumor types.Science. 1994;264:436–439.

    Article  PubMed  CAS  Google Scholar 

  67. Nobori T, Miura K, Wu DJ, Lois A, Takabayashi K, Carson DA. Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers.Nature. 1994;368:753–756.

    Article  PubMed  CAS  Google Scholar 

  68. Hannon GJ, Beach D. p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest.Nature. 1994;371:257–261.

    Article  PubMed  CAS  Google Scholar 

  69. Ogawa S, Hangaishi A, Miyawaki S, et al. Loss of the cyclin-dependent kinase 4-inhibitor (CDK41; p16; MTS1) gene is frequent in, and highly specific to lymphoid tumors in human hematopoietic malignancies.Blood. 1995;86:1548–1556.

    PubMed  CAS  Google Scholar 

  70. Herman JG, Jen J, Merlo A, Baylin SB. Hypermethylation-associated inactivation indicates a tumor suppressor role for p15INK4B.Cancer Res. 1996;56:722–727.

    PubMed  CAS  Google Scholar 

  71. Uchida T, Kinoshita T, Nagai H, et al. Hypermethylation of the p15INK4B gene in myelodysplastic syndromes.Blood. 1997;90:1403–1409.

    PubMed  CAS  Google Scholar 

  72. 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.

    PubMed  CAS  Google Scholar 

  73. Wijermans P, Lubbert M, Verhoef G, et al. Low-dose 5-aza-2′-deoxycytidine, a DNA hypomethylating agent, for the treatment of high-risk myelodysplastic syndrome: a multicenter phase II study in elderly patients.J Clin Oncol. 2000;18:956–962.

    PubMed  CAS  Google Scholar 

  74. Lubbert M, Wijermans P, Kunzmann R, et al. Cytogenetic responses in high-risk myelodysplastic syndrome following low-dose treatment with the DNA methylation inhibitor 5-aza-2′-deoxycytidine.Br J Haematol. 2001;114:349–357.

    Article  PubMed  CAS  Google Scholar 

  75. Bos JL. ras oncogenes in human cancer: a review. Cancer Res. 1989;49:4682–4689.

    PubMed  CAS  Google Scholar 

  76. Deng C, Zhang P, Harper JW, Elledge SJ, Leder P. Mice lacking p21CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control.Cell. 1995;82:675–684.

    Article  PubMed  CAS  Google Scholar 

  77. Okuda T, van Deursen J, Hiebert SW, Grosveld G, Downing JR. AML1, the target of multiple chromosomal translocations in human leukemia, is essential for normal fetal liver hematopoiesis.Cell. 1996;84:321–330.

    Article  PubMed  CAS  Google Scholar 

  78. Wang Q, Stacy T, Miller JD, et al. The CBFbeta subunit is essential for CBFalpha2 (AML1) function in vivo.Cell. 1996; 87:697–708.

    Article  PubMed  CAS  Google Scholar 

  79. Collins SJ, Ulmer J, Purton LE, Darlington G. Multipotent hematopoietic cell lines derived from C/EBPalpha (−/−) knockout mice display granulocyte macrophage-colony-stimulating factor, granulocyte-colony-stimulating factor, and retinoic acid- induced granulocytic differentiation.Blood. 2001;98: 2381–2388.

    Google Scholar 

  80. Wang LC, Swat W, Fujiwara Y, et al. The TEL/ETV6 gene is required specifically for hematopoiesis in the bone marrow.Genes Dev. 1998;12:2392–2402.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Graduate School of Medicine, University of Tokyo, Tokyo, Japan

    Hisamaru Hirai

Authors
  1. Hisamaru Hirai
    View author publications

    You can also search for this author in PubMed Google Scholar

About this article

Cite this article

Hirai, H. Molecular pathogenesis of MDS. Int J Hematol 76 (Suppl 2), 213–221 (2002). https://doi.org/10.1007/BF03165120

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03165120

Key Words

Search

Navigation