Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Cytogenetics and molecular genetics of myelodysplastic syndromes

Yanming Zhang, MD
Michelle M Le Beau, PhD
Section Editor
Richard A Larson, MD
Deputy Editor
Alan G Rosmarin, MD


The myelodysplastic syndromes (MDS) encompass a series of hematologic conditions characterized by chronic cytopenias (anemia, neutropenia, thrombocytopenia) accompanied by abnormal cellular maturation. As a result, patients with MDS are at risk for symptomatic anemia, infection, and bleeding, as well as progression to acute myeloid leukemia (AML), which is often refractory to standard treatment.

The pathobiology of MDS is complex and not fully understood; however, alterations in the function of the bone marrow microenvironment, or niche, as well as the hematopoietic stem cells have been implicated. The development of MDS involves a series of genetic changes in a hematopoietic stem cell. These changes alter normal hematopoietic growth and differentiation, resulting in an accumulation of abnormal, immature myeloid cells in the bone marrow and the impairment of normal hematopoiesis. Advances in the identification of recurring chromosomal abnormalities and gene alterations have provided insight into the pathobiology of MDS.

Specific cytogenetic abnormalities identified by karyotype analysis or fluorescence in situ hybridization (FISH) analysis have prognostic significance for patients with primary MDS and affect treatment planning. Certain gene mutations also confer prognostic significance in adult patients with MDS, but it is not yet clear how to incorporate these changes into treatment planning. Even those patients without obvious abnormalities detected by karyotypic analysis, FISH, or gene mutation analyses likely have abnormalities in gene expression profiles or have acquired copy number alterations that may help to identify genes important for the pathogenesis of MDS.

Characteristic chromosomal abnormalities have also been identified in patients who developed MDS or AML (often preceded by MDS) after chemotherapy and/or radiation therapy for an earlier disorder, such as Hodgkin lymphoma, non-Hodgkin lymphoma (NHL), or a solid tumor, as well as non-malignant disorders, such as rheumatoid arthritis, or following organ transplantation (table 1). This subject is discussed separately. (See "Cytogenetics in acute myeloid leukemia", section on 'Therapy-related myeloid neoplasms (t-MDS/t-AML)'.)

The cytogenetic and molecular genetic features of primary MDS and the use of genetic studies in predicting both progression to AML and survival will be reviewed here. An overview of cytogenetic abnormalities in hematologic malignancies (including definitions, methods of detection, the genetic consequences of chromosomal translocations) and a more detailed discussion of the prognosis of MDS are presented separately. (See "Prognosis of the myelodysplastic syndromes in adults" and "General aspects of cytogenetic analysis in hematologic malignancies" and "Chromosomal translocations, deletions, and inversions".)

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Oct 2017. | This topic last updated: Nov 02, 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Haase D, Germing U, Schanz J, et al. New insights into the prognostic impact of the karyotype in MDS and correlation with subtypes: evidence from a core dataset of 2124 patients. Blood 2007; 110:4385.
  2. Pozdnyakova O, Miron PM, Tang G, et al. Cytogenetic abnormalities in a series of 1,029 patients with primary myelodysplastic syndromes: a report from the US with a focus on some undefined single chromosomal abnormalities. Cancer 2008; 113:3331.
  3. Bejar R, Levine R, Ebert BL. Unraveling the molecular pathophysiology of myelodysplastic syndromes. J Clin Oncol 2011; 29:504.
  4. Olney HJ, Le Beau MM. Evaluation of recurring cytogenetic abnormalities in the treatment of myelodysplastic syndromes. Leuk Res 2007; 31:427.
  5. Schanz J, Tüchler H, Solé F, et al. New comprehensive cytogenetic scoring system for primary myelodysplastic syndromes (MDS) and oligoblastic acute myeloid leukemia after MDS derived from an international database merge. J Clin Oncol 2012; 30:820.
  6. Lewis S, Oscier D, Boultwood J, et al. Hematological features of patients with myelodysplastic syndromes associated with a chromosome 5q deletion. Am J Hematol 1995; 49:194.
  7. Jabbour E, Takahashi K, Wang X, et al. Acquisition of cytogenetic abnormalities in patients with IPSS defined lower-risk myelodysplastic syndrome is associated with poor prognosis and transformation to acute myelogenous leukemia. Am J Hematol 2013; 88:831.
  8. Bernasconi P. Molecular pathways in myelodysplastic syndromes and acute myeloid leukemia: relationships and distinctions-a review. Br J Haematol 2008; 142:695.
  9. Steensma DP, List AF. Genetic testing in the myelodysplastic syndromes: molecular insights into hematologic diversity. Mayo Clin Proc 2005; 80:681.
  10. Bacher U, Haferlach T, Kern W, et al. The impact of cytomorphology, cytogenetics, molecular genetics, and immunophenotyping in a comprehensive diagnostic workup of myelodysplastic syndromes. Cancer 2009; 115:4524.
  11. Greenberg PL, Tuechler H, Schanz J, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood 2012; 120:2454.
  12. Wiktor A, Rybicki BA, Piao ZS, et al. Clinical significance of Y chromosome loss in hematologic disease. Genes Chromosomes Cancer 2000; 27:11.
  13. Velloso ER, Michaux L, Ferrant A, et al. Deletions of the long arm of chromosome 7 in myeloid disorders: loss of band 7q32 implies worst prognosis. Br J Haematol 1996; 92:574.
  14. Boultwood J, Lewis S, Wainscoat JS. The 5q-syndrome. Blood 1994; 84:3253.
  15. Jerez A, Gondek LP, Jankowska AM, et al. Topography, clinical, and genomic correlates of 5q myeloid malignancies revisited. J Clin Oncol 2012; 30:1343.
  16. Boultwood J, Fidler C, Strickson AJ, et al. Narrowing and genomic annotation of the commonly deleted region of the 5q- syndrome. Blood 2002; 99:4638.
  17. Horrigan SK, Arbieva ZH, Xie HY, et al. Delineation of a minimal interval and identification of 9 candidates for a tumor suppressor gene in malignant myeloid disorders on 5q31. Blood 2000; 95:2372.
  18. Liu TX, Becker MW, Jelinek J, et al. Chromosome 5q deletion and epigenetic suppression of the gene encoding alpha-catenin (CTNNA1) in myeloid cell transformation. Nat Med 2007; 13:78.
  19. Zhao N, Stoffel A, Wang PW, et al. Molecular delineation of the smallest commonly deleted region of chromosome 5 in malignant myeloid diseases to 1-1.5 Mb and preparation of a PAC-based physical map. Proc Natl Acad Sci U S A 1997; 94:6948.
  20. Pedersen B. 5q(-)survival: importance of gender and deleted 5q bands and survival analysis based on 324 published cases. Leuk Lymphoma 1998; 31:325.
  21. Gondek LP, Tiu R, O'Keefe CL, et al. Chromosomal lesions and uniparental disomy detected by SNP arrays in MDS, MDS/MPD, and MDS-derived AML. Blood 2008; 111:1534.
  22. Graubert TA, Payton MA, Shao J, et al. Integrated genomic analysis implicates haploinsufficiency of multiple chromosome 5q31.2 genes in de novo myelodysplastic syndromes pathogenesis. PLoS One 2009; 4:e4583.
  23. Heinrichs S, Kulkarni RV, Bueso-Ramos CE, et al. Accurate detection of uniparental disomy and microdeletions by SNP array analysis in myelodysplastic syndromes with normal cytogenetics. Leukemia 2009; 23:1605.
  24. Boultwood J, Pellagatti A, Cattan H, et al. Gene expression profiling of CD34+ cells in patients with the 5q- syndrome. Br J Haematol 2007; 139:578.
  25. Ebert BL, Pretz J, Bosco J, et al. Identification of RPS14 as a 5q- syndrome gene by RNA interference screen. Nature 2008; 451:335.
  26. Pellagatti A, Hellström-Lindberg E, Giagounidis A, et al. Haploinsufficiency of RPS14 in 5q- syndrome is associated with deregulation of ribosomal- and translation-related genes. Br J Haematol 2008; 142:57.
  27. Mohamedali A, Mufti GJ. Van-den Berghe's 5q- syndrome in 2008. Br J Haematol 2009; 144:157.
  28. Starczynowski DT, Kuchenbauer F, Argiropoulos B, et al. Identification of miR-145 and miR-146a as mediators of the 5q- syndrome phenotype. Nat Med 2010; 16:49.
  29. Liu Y, Asai T, Nimer SD. Myelodysplasia: battle in the bone marrow. Nat Med 2010; 16:30.
  30. Barlow JL, Drynan LF, Hewett DR, et al. A p53-dependent mechanism underlies macrocytic anemia in a mouse model of human 5q- syndrome. Nat Med 2010; 16:59.
  31. Valencia A, Cervera J, Such E, et al. Lack of RPS14 promoter aberrant methylation supports the haploinsufficiency model for the 5q- syndrome. Blood 2008; 112:918.
  32. Schneider RK, Ademà V, Heckl D, et al. Role of casein kinase 1A1 in the biology and targeted therapy of del(5q) MDS. Cancer Cell 2014; 26:509.
  33. Smith AE, Kulasekararaj AG, Jiang J, et al. CSNK1A1 mutations and isolated del(5q) abnormality in myelodysplastic syndrome: a retrospective mutational analysis. Lancet Haematol 2015; 2:e212.
  34. Krönke J, Fink EC, Hollenbach PW, et al. Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS. Nature 2015; 523:183.
  35. Wang J, Fernald AA, Anastasi J, et al. Haploinsufficiency of Apc leads to ineffective hematopoiesis. Blood 2010; 115:3481.
  36. Lane SW, Sykes SM, Al-Shahrour F, et al. The Apc(min) mouse has altered hematopoietic stem cell function and provides a model for MPD/MDS. Blood 2010; 115:3489.
  37. Joslin JM, Fernald AA, Tennant TR, et al. Haploinsufficiency of EGR1, a candidate gene in the del(5q), leads to the development of myeloid disorders. Blood 2007; 110:719.
  38. Stoddart A, Fernald AA, Wang J, et al. Haploinsufficiency of del(5q) genes, Egr1 and Apc, cooperate with Tp53 loss to induce acute myeloid leukemia in mice. Blood 2014; 123:1069.
  39. Kantarjian H, O'Brien S, Ravandi F, et al. The heterogeneous prognosis of patients with myelodysplastic syndrome and chromosome 5 abnormalities: how does it relate to the original lenalidomide experience in MDS? Cancer 2009; 115:5202.
  40. Xu F, Li X, Wu L, et al. Overexpression of the EZH2, RING1 and BMI1 genes is common in myelodysplastic syndromes: relation to adverse epigenetic alteration and poor prognostic scoring. Ann Hematol 2011; 90:643.
  41. Makishima H, Jankowska AM, Tiu RV, et al. Novel homo- and hemizygous mutations in EZH2 in myeloid malignancies. Leukemia 2010; 24:1799.
  42. Nikoloski G, Langemeijer SM, Kuiper RP, et al. Somatic mutations of the histone methyltransferase gene EZH2 in myelodysplastic syndromes. Nat Genet 2010; 42:665.
  43. Malcovati L, Germing U, Kuendgen A, et al. Time-dependent prognostic scoring system for predicting survival and leukemic evolution in myelodysplastic syndromes. J Clin Oncol 2007; 25:3503.
  44. Bench AJ, Nacheva EP, Hood TL, et al. Chromosome 20 deletions in myeloid malignancies: reduction of the common deleted region, generation of a PAC/BAC contig and identification of candidate genes. UK Cancer Cytogenetics Group (UKCCG). Oncogene 2000; 19:3902.
  45. Wang PW, Eisenbart JD, Espinosa R 3rd, et al. Refinement of the smallest commonly deleted segment of chromosome 20 in malignant myeloid diseases and development of a PAC-based physical and transcription map. Genomics 2000; 67:28.
  46. Swerdlow SH, Campo E, Harris NL, et al. World Health Organization classification of tumours of haematopoietic and lymphoid tissues, IARC Press, Lyon 2008.
  47. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016; 127:2391.
  48. Nimer SD. Clinical management of myelodysplastic syndromes with interstitial deletion of chromosome 5q. J Clin Oncol 2006; 24:2576.
  49. Vardiman JW, Brunning RD, Arber DA, et al. Introduction and overview of the classification of the myeloid neoplasms. In: WHO classification of tumors of hematopoietic and lymphoid tissues, Swerdlow SH, Campo E, Harris NL, et al (Eds), WHO press, 2008. p.18.
  50. List A, Dewald G, Bennett J, et al. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med 2006; 355:1456.
  51. Sanz GF, Sanz MA, Vallespí T, et al. Two regression models and a scoring system for predicting survival and planning treatment in myelodysplastic syndromes: a multivariate analysis of prognostic factors in 370 patients. Blood 1989; 74:395.
  52. Solé F, Espinet B, Sanz GF, et al. Incidence, characterization and prognostic significance of chromosomal abnormalities in 640 patients with primary myelodysplastic syndromes. Grupo Cooperativo Español de Citogenética Hematológica. Br J Haematol 2000; 108:346.
  53. 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.
  54. Pfeilstöcker M, Tuechler H, Sanz G, et al. Time-dependent changes in mortality and transformation risk in MDS. Blood 2016; 128:902.
  55. Bejar R, Stevenson K, Abdel-Wahab O, et al. Clinical effect of point mutations in myelodysplastic syndromes. N Engl J Med 2011; 364:2496.
  56. Papaemmanuil E, Gerstung M, Malcovati L, et al. Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood 2013; 122:3616.
  57. Haferlach T, Nagata Y, Grossmann V, et al. Landscape of genetic lesions in 944 patients with myelodysplastic syndromes. Leukemia 2014; 28:241.
  58. Mossner M, Jann JC, Wittig J, et al. Mutational hierarchies in myelodysplastic syndromes dynamically adapt and evolve upon therapy response and failure. Blood 2016; 128:1246.
  59. Shen L, Kantarjian H, Guo Y, et al. DNA methylation predicts survival and response to therapy in patients with myelodysplastic syndromes. J Clin Oncol 2010; 28:605.
  60. Jiang Y, Dunbar A, Gondek LP, et al. Aberrant DNA methylation is a dominant mechanism in MDS progression to AML. Blood 2009; 113:1315.
  61. Ito S, D'Alessio AC, Taranova OV, et al. Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature 2010; 466:1129.
  62. Delhommeau F, Dupont S, Della Valle V, et al. Mutation in TET2 in myeloid cancers. N Engl J Med 2009; 360:2289.
  63. Kosmider O, Gelsi-Boyer V, Cheok M, et al. TET2 mutation is an independent favorable prognostic factor in myelodysplastic syndromes (MDSs). Blood 2009; 114:3285.
  64. Walter MJ, Ding L, Shen D, et al. Recurrent DNMT3A mutations in patients with myelodysplastic syndromes. Leukemia 2011; 25:1153.
  65. Roller A, Grossmann V, Bacher U, et al. Landmark analysis of DNMT3A mutations in hematological malignancies. Leukemia 2013; 27:1573.
  66. Ley TJ, Ding L, Walter MJ, et al. DNMT3A mutations in acute myeloid leukemia. N Engl J Med 2010; 363:2424.
  67. Thol F, Weissinger EM, Krauter J, et al. IDH1 mutations in patients with myelodysplastic syndromes are associated with an unfavorable prognosis. Haematologica 2010; 95:1668.
  68. Kosmider O, Gelsi-Boyer V, Slama L, et al. Mutations of IDH1 and IDH2 genes in early and accelerated phases of myelodysplastic syndromes and MDS/myeloproliferative neoplasms. Leukemia 2010; 24:1094.
  69. Figueroa ME, Abdel-Wahab O, Lu C, et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 2010; 18:553.
  70. Gelsi-Boyer V, Trouplin V, Adélaïde J, et al. Mutations of polycomb-associated gene ASXL1 in myelodysplastic syndromes and chronic myelomonocytic leukaemia. Br J Haematol 2009; 145:788.
  71. Boultwood J, Perry J, Pellagatti A, et al. Frequent mutation of the polycomb-associated gene ASXL1 in the myelodysplastic syndromes and in acute myeloid leukemia. Leukemia 2010; 24:1062.
  72. Carbuccia N, Murati A, Trouplin V, et al. Mutations of ASXL1 gene in myeloproliferative neoplasms. Leukemia 2009; 23:2183.
  73. Fisher CL, Randazzo F, Humphries RK, Brock HW. Characterization of Asxl1, a murine homolog of Additional sex combs, and analysis of the Asx-like gene family. Gene 2006; 369:109.
  74. Papaemmanuil E, Cazzola M, Boultwood J, et al. Somatic SF3B1 mutation in myelodysplasia with ring sideroblasts. N Engl J Med 2011; 365:1384.
  75. Makishima H, Visconte V, Sakaguchi H, et al. Mutations in the spliceosome machinery, a novel and ubiquitous pathway in leukemogenesis. Blood 2012; 119:3203.
  76. Damm F, Kosmider O, Gelsi-Boyer V, et al. Mutations affecting mRNA splicing define distinct clinical phenotypes and correlate with patient outcome in myelodysplastic syndromes. Blood 2012; 119:3211.
  77. Yoshida K, Sanada M, Shiraishi Y, et al. Frequent pathway mutations of splicing machinery in myelodysplasia. Nature 2011; 478:64.
  78. Graubert TA, Shen D, Ding L, et al. Recurrent mutations in the U2AF1 splicing factor in myelodysplastic syndromes. Nat Genet 2011; 44:53.
  79. Visconte V, Makishima H, Jankowska A, et al. SF3B1, a splicing factor is frequently mutated in refractory anemia with ring sideroblasts. Leukemia 2012; 26:542.
  80. Malcovati L, Papaemmanuil E, Bowen DT, et al. Clinical significance of SF3B1 mutations in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms. Blood 2011; 118:6239.
  81. Patnaik MM, Lasho TL, Hodnefield JM, et al. SF3B1 mutations are prevalent in myelodysplastic syndromes with ring sideroblasts but do not hold independent prognostic value. Blood 2012; 119:569.
  82. Meggendorfer M, Roller A, Haferlach T, et al. SRSF2 mutations in 275 cases with chronic myelomonocytic leukemia (CMML). Blood 2012; 120:3080.
  83. Wu SJ, Kuo YY, Hou HA, et al. The clinical implication of SRSF2 mutation in patients with myelodysplastic syndrome and its stability during disease evolution. Blood 2012; 120:3106.
  84. Thol F, Kade S, Schlarmann C, et al. Frequency and prognostic impact of mutations in SRSF2, U2AF1, and ZRSR2 in patients with myelodysplastic syndromes. Blood 2012; 119:3578.
  85. Chen CY, Lin LI, Tang JL, et al. RUNX1 gene mutation in primary myelodysplastic syndrome--the mutation can be detected early at diagnosis or acquired during disease progression and is associated with poor outcome. Br J Haematol 2007; 139:405.
  86. Steensma DP, Gibbons RJ, Mesa RA, et al. Somatic point mutations in RUNX1/CBFA2/AML1 are common in high-risk myelodysplastic syndrome, but not in myelofibrosis with myeloid metaplasia. Eur J Haematol 2005; 74:47.
  87. Tang JL, Hou HA, Chen CY, et al. AML1/RUNX1 mutations in 470 adult patients with de novo acute myeloid leukemia: prognostic implication and interaction with other gene alterations. Blood 2009; 114:5352.
  88. Christiansen DH, Andersen MK, Pedersen-Bjergaard J. Mutations with loss of heterozygosity of p53 are common in therapy-related myelodysplasia and acute myeloid leukemia after exposure to alkylating agents and significantly associated with deletion or loss of 5q, a complex karyotype, and a poor prognosis. J Clin Oncol 2001; 19:1405.
  89. Kaneko H, Misawa S, Horiike S, et al. TP53 mutations emerge at early phase of myelodysplastic syndrome and are associated with complex chromosomal abnormalities. Blood 1995; 85:2189.
  90. 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.
  91. Horiike S, Kita-Sasai Y, Nakao M, Taniwaki M. Configuration of the TP53 gene as an independent prognostic parameter of myelodysplastic syndrome. Leuk Lymphoma 2003; 44:915.
  92. Kita-Sasai Y, Horiike S, Misawa S, et al. International prognostic scoring system and TP53 mutations are independent prognostic indicators for patients with myelodysplastic syndrome. Br J Haematol 2001; 115:309.
  93. Zeleznik-Le NJ, Nucifora G, Rowley JD. The molecular biology of myeloproliferative disorders as revealed by chromosomal abnormalities. Semin Hematol 1995; 32:201.
  94. Ahuja HG, Foti A, Bar-Eli M, Cline MJ. The pattern of mutational involvement of RAS genes in human hematologic malignancies determined by DNA amplification and direct sequencing. Blood 1990; 75:1684.
  95. Bartram CR. Molecular genetic aspects of myelodysplastic syndromes. Hematol Oncol Clin North Am 1992; 6:557.
  96. Nakagawa T, Saitoh S, Imoto S, et al. Multiple point mutation of N-ras and K-ras oncogenes in myelodysplastic syndrome and acute myelogenous leukemia. Oncology 1992; 49:114.
  97. Bos JL. ras oncogenes in human cancer: a review. Cancer Res 1989; 49:4682.
  98. Shih LY, Lin TL, Wang PN, et al. Internal tandem duplication of fms-like tyrosine kinase 3 is associated with poor outcome in patients with myelodysplastic syndrome. Cancer 2004; 101:989.
  99. Georgiou G, Karali V, Zouvelou C, et al. Serial determination of FLT3 mutations in myelodysplastic syndrome patients at diagnosis, follow up or acute myeloid leukaemia transformation: incidence and their prognostic significance. Br J Haematol 2006; 134:302.
  100. Mohamedali A, Gäken J, Twine NA, et al. Prevalence and prognostic significance of allelic imbalance by single-nucleotide polymorphism analysis in low-risk myelodysplastic syndromes. Blood 2007; 110:3365.
  101. Langemeijer SM, Kuiper RP, Berends M, et al. Acquired mutations in TET2 are common in myelodysplastic syndromes. Nat Genet 2009; 41:838.