Molecular Genetics of Myelodysplastic Syndromes

Rafael Bejar, University of California, San Diego, La Jolla, California, USA
David P Steensma, Dana‐Farber Cancer Institute, Boston, Massachusetts, USA

Published online: November 2012

DOI: 10.1002/9780470015902.a0023872

Myelodysplastic syndromes (MDS) are a group of clonal haematopoietic disorders characterised clinically by inefficient haematopoiesis, cytopenias of the peripheral blood and a risk of progression to acute myeloid leukaemia (AML). Molecularly, MDS can be associated with a wide range of acquired chromosomal abnormalities, epigenetic alterations and single gene mutations. These abnormalities affect diverse molecular pathways including ribonucleic acid (RNA) splicing machinery, epigenetic modifiers, haematopoietic transcription factors, receptor tyrosine kinase signalling, cell cycle regulation and apoptosis. The particular combination of somatic genetic lesions in any given patient will influence how their disease is manifested, and together with individual background germline genotype may explain much of the clinical heterogeneity associated with MDS. Here, the common genetic abnormalities that underlie MDS and how these abnormalities influence the development and progression of these disorders have been reviewed.

Key Concepts:

  • MDS represent a collection of disorders marked by abnormal, inefficient haematopoiesis, cytopenias of the peripheral blood and a predisposition for progression to AML.
  • Like other haematopoietic malignancies, MDS arise from the clonal expansion of a single, abnormal haematopoietic cell.
  • The abnormal MDS cells that maintain the disease have the ability to self-renew and clonally expand because they have a selective growth advantage compared to their normal counterparts.
  • Impaired haematopoietic differentiation in MDS can lead to cytopenias or to the production of terminally differentiated cells with abnormal function.
  • A combination of somatic genetic abnormalities (acquired changes to the deoxyribonucleic acid (DNA) coding sequence), epigenetic abnormalities (heritable changes in gene expression) and marrow microenvironmental abnormalities contribute to the development and progression of MDS.
  • Approximately, 50% of MDS cells have a chromosomal abnormality detectable by routine metaphase karyotype analysis.
  • More than 75% of patients have acquired mutations in one or more genes known to be recurrently altered in MDS.
  • Recurrent mutations in MDS implicate several molecular pathways in the development and progression of disease including; altered RNA splicing mechanisms, epigenetic changes in DNA methylation and histone modifications, activation of growth factor signalling cascades, impaired differentiation and abnormal regulation of cell cycle and apoptosis.
  • Acquired mutations in several MDS genes have prognostic significance that is independent of clinically based prognostic scoring systems.
  • Chromosomal abnormalities and mutations in some genes can predict response to specific therapies used to treat patients with MDS.

Keywords: myelodysplastic syndromes; somatic mutations; refractory anaemia; thrombocytopenia; splicing factors; epigenetics; ring sideroblasts; cytogenetic abnormalities; acute myeloid leukaemia; stem cell transplantation; hypomethylating agents; azacitidine; decitabine; lenalidomide

Figure 1. Identification of commonly retained regions of chromosome 5q and their association with disease subtypes. Mapping of deletions detected by single-nucleotide polymorphism array in the cohort separated according the involvement (right) or not (left) of 5q-syndrome commonly retained regions. Deletions have been coloured depending on the IPSS risk group at diagnosis (MDS) or de novo or secondary origin (AML). Low-risk MDS includes low and intermediate-1 IPSS groups. High-risk MDS includes intermediate 2 and high-risk IPSS groups. Reprinted with permission from Jerez et al. (2012a) © 2012 American Society of Clinical Oncology. All rights reserved.
Figure 2. (a) Proportions of MDS patients grouped by karyotype and somatic mutation status of the genes listed in (b). (b) Distribution of mutations in patients with one or more mutations. Each column represents a single sample from a patient with MDS. Each coloured bar represents a mutation of the gene(s) in that row. Darker bars indicate two or more distinct mutations in a sample. Adapted from data presented in Bejar et al. (2011) Copyright © 2011 Massachusetts Medical Society and in the Bejar et al. (2012) Validation of a Prognostic Model and Impact of Mutations on Lower-Risk Myelodysplastic Syndromes. Journal of Clinical Oncology, doi: 10.1200/JCO.2011.40.7379 (epub ahead of print on 6 August 2012). Copyright © 2012, with permission from American Society of Clinical Oncology. (c) Circos plot made from the data in (b) showing overlap between pairs of mutations in different genes. The largely mutually exclusive splicing factors are shown in red, genes involved in DNA methylation are shown in yellow, histone-associated genes are shown in blue, and transcription factors, tyrosine kinase pathway (TKP), and other genes are shown in black. The portion of each outer bar without a ribbon represents the fraction of patients that only had a mutation of that gene. For example, more than half of TP53 mutant patients had no other mutations, whereas almost every patient with an EZH2 mutation had a mutation in at least on other gene.
Figure 3. (a) Mutation profiles for MDS samples with TP53 mutations and/or complex cytogenetics. Coloured bars represent mutations in the gene groups listed to the left. Each column represents an individual sample. Darker bars indicate compound heterozygous mutations. Black bars in the karyotype row indicate complex cytogenetics, white is normal or –Y, red is del(5q) alone, and grey is some other abnormality. Reprinted with permission from Bejar et al., 2011. Copyright © 2011 Massachusetts Medical Society (b) Survival curves for patients stratified by complex karyotype and TP53 mutation status. Reprinted with permission from Bejar et al., 2011. Copyright © 2011 Massachusetts Medical Society.
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 References
    Barjesteh van Waalwijk van Doorn-Khosrovani S, Erpelinck C, van Putten WLJ et al. (2003) High EVI1 expression predicts poor survival in acute myeloid leukemia: a study of 319 de novo AML patients. Blood 101: 837–845.
    Barlow JL, Drynan LF, Hewett DR et al. (2010) A p53-dependent mechanism underlies macrocytic anemia in a mouse model of human 5q- syndrome. Nature Medicine 16: 59–66.
    Barrett AJ and Sloand E (2009) Autoimmune mechanisms in the pathophysiology of myelodysplastic syndromes and their clinical relevance. Haematologica 94: 449–451.
    Bejar R, Stevenson K, Abdel-Wahab O et al. (2011) Clinical effect of point mutations in myelodysplastic syndromes. New England Journal of Medicine 364(26): 2496–2506.
    Bejar R, Stevenson KE, Caughey BA et al. (2012) Validation of a prognostic model and the impact of mutations in patients with lower-risk myelodysplastic syndromes. Journal of Clinical Oncology. doi:10.1200/JCO.2011.40.7379. [Epub ahead of print].
    Bench AJ, Nacheva EP, Hood TL et al. (2000) 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 19: 3902–3913.
    Boultwood J, Pellagatti A and Wainscoat JS (2012) 5q-syndrome. Current Pharmaceutical Design 18: 3180–3183.
    Buonamici S, Li D, Chi Y et al. (2004) EVI1 induces myelodysplastic syndrome in mice. Journal of Clinical Investigation 114: 713–719.
    Carbuccia N, Murati A, Trouplin V et al. (2009) Mutations of ASXL1 gene in myeloproliferative neoplasms. Leukemia 23: 2183–2186.
    Challen GA, Sun D, Jeong M et al. (2012) Dnmt3a is essential for hematopoietic stem cell differentiation. Nature Genetics 44: 23–31.
    Chen TH, Kambal A, Krysiak K et al. (2011) Knockdown of Hspa9, a del(5q31.2) gene, results in a decrease in hematopoietic progenitors in mice. Blood 117: 1530–1539.
    Cheng K, Sportoletti P, Ito K et al. (2010) The cytoplasmic NPM mutant induces myeloproliferation in a transgenic mouse model. Blood 115: 3341–3345.
    Cordoba I, Gonzalez-Porras JR, Nomdedeu B et al. (2012) Better prognosis for patients with del(7q) than for patients with monosomy 7 in myelodysplastic syndrome. Cancer 118: 127–133.
    Craven SE, French D, Ye W, de Sauvage F and Rosenthal A (2005) Loss of Hspa9b in zebrafish recapitulates the ineffective hematopoiesis of the myelodysplastic syndrome. Blood 105(9): 3528–3534.
    Damm F, Thol F, Kosmider O et al. (2012a) SF3B1 mutations in myelodysplastic syndromes: clinical associations and prognostic implications. Leukemia 26: 1137–1140.
    Damm F, Kosmider O, Gelsi-Boyer V et al. (2012b) Mutations affecting mRNA splicing define distinct clinical phenotypes and correlate with patient outcome in myelodysplastic syndromes. Blood 119: 3211–3218.
    Dawson MA, Bannister AJ, Gottgens B et al. (2009) JAK2 phosphorylates histone H3Y41 and excludes HP1[agr] from chromatin. Nature 461: 819–822.
    Du Y, Jenkins NA and Copeland NG (2005) Insertional mutagenesis identifies genes that promote the immortalization of primary bone marrow progenitor cells. Blood 106: 3932–3939.
    Dutt S, Narla A, Lin K et al. (2011) Haploinsufficiency for ribosomal protein genes causes selective activation of p53 in human erythroid progenitor cells. Blood 117: 2567–2576.
    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.
    Ernst T, Chase AJ, Score J et al. (2010) Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nature Genetics 42: 722–726.
    Figueroa ME, Abdel-Wahab O, Lu C et al. (2010) Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18: 553–567.
    Fisher CL, Pineault N, Brookes C et al. (2010) Loss-of-function Additional sex combs like 1 mutations disrupt hematopoiesis but do not cause severe myelodysplasia or leukemia. Blood 115: 38–46.
    Gelsi-Boyer V, Trouplin V, Roquain J et al. (2010) ASXL1 mutation is associated with poor prognosis and acute transformation in chronic myelomonocytic leukaemia. British Journal of Haematology 151: 365–375.
    Gelsi-Boyer V, Trouplin V, Adelaide J et al. (2009) Mutations of polycomb-associated gene ASXL1 in myelodysplastic syndromes and chronic myelomonocytic leukaemia. British Journal of Haematology 145: 788–800.
    Gondek LP, Haddad AS, O'Keefe CL et al. (2007) Detection of cryptic chromosomal lesions including acquired segmental uniparental disomy in advanced and low-risk myelodysplastic syndromes. Experimental Hematology 35: 1728–1738.
    Gondek LP, Tiu R, O'Keefe CL et al. (2008) Chromosomal lesions and uniparental disomy detected by SNP arrays in MDS, MDS/MPD, and MDS-derived AML. Blood 111: 1534–1542.
    Graubert TA, Shen D, Ding L et al. (2012) Recurrent mutations in the U2AF1 splicing factor in myelodysplastic syndromes. Nature Genetics 44: 53–57.
    Greenberg P, Cox C, LeBeau MM et al. (1997) International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 89: 2079–2088.
    Greenberg PL, Tuechler H, Schanz J et al. (2012) Revised International Prognostic Scoring System (IPSS-R) for myelodysplastic syndromes. Blood. doi:10.1182/blood-2012-03-420489.
    Grisendi S, Bernardi R, Rossi M et al. (2005) Role of nucleophosmin in embryonic development and tumorigenesis. Nature 437: 147–153.
    Growney JD, Shigematsu H, Li Z et al. (2005) Loss of Runx1 perturbs adult hematopoiesis and is associated with a myeloproliferative phenotype. Blood 106: 494–504.
    Haase D, Germing U, Schanz J et al. (2007) New insights into the prognostic impact of the karyotype in MDS and correlation with subtypes: evidence from a core dataset of 2124 patients. Blood 110: 4385–4395.
    Hahn CN, Chong CE, Carmichael CL et al. (2011) Heritable GATA2 mutations associated with familial myelodysplastic syndrome and acute myeloid leukemia. Nature Genetics 43: 1012–1017.
    Harada Y and Harada H (2009) Molecular pathways mediating MDS/AML with focus on AML1/RUNX1 point mutations. Journal of Cellular Physiology 220: 16–20.
    Harada H, Harada Y, Niimi H et al. (2004) High incidence of somatic mutations in the AML1/RUNX1 gene in myelodysplastic syndrome and low blast percentage myeloid leukemia with myelodysplasia. Blood 103: 2316–2324.
    Heinrichs S, Kulkarni RV, Bueso-Ramos CE et al. (2009) Accurate detection of uniparental disomy and microdeletions by SNP array analysis in myelodysplastic syndromes with normal cytogenetics. Leukemia 23: 1605–1613.
    Heinrichs S, Conover L, Bueso-Ramos CE et al. (2010) MYBL2 is a candidate tumor suppressor gene in MDS. ASH Annual Meeting Abstracts 116: 1865.
    Ho CY, Otterud B, Legare RD et al. (1996) Linkage of a familial platelet disorder with a propensity to develop myeloid malignancies to human chromosome 21q22.1-22.2. Blood 87: 5218–5224.
    Isono K, Mizutani-Koseki Y, Komori T , Schmidt-Zachmann MS and Koseki H (2005) Mammalian polycomb-mediated repression of Hox genes requires the essential spliceosomal protein Sf3b1. Genes and Development 19(5): 536–541.
    Ito S, D'Alessio AC, Taranova OV et al. (2010) Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature 466: 1129–1133.
    Ito S, Shen L, Dai Q et al. (2011) Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science 333: 1300–1303.
    Jädersten M, Saft L, Pellagatti A et al. (2009) Clonal heterogeneity in the 5q- syndrome: p53 expressing progenitors prevail during lenalidomide treatment and expand at disease progression. Haematologica 94: 1762–1766.
    Jädersten M, Saft L, Smith A et al. (2011) TP53 mutations in low-risk myelodysplastic syndromes with del(5q) predict disease progression. Journal of Clinical Oncology 29: 1971–1979.
    Jankowska AM, Makishima H, Tiu RV et al. (2011) Mutational spectrum analysis of chronic myelomonocytic leukemia includes genes associated with epigenetic regulation: UTX, EZH2, and DNMT3A. Blood 118: 3932–3941.
    Jerez A, Gondek LP, Jankowska AM et al. (2012a) Topography, clinical, and genomic correlates of 5q myeloid malignancies revisited. Journal of Clinical Oncology 30: 1343–1349.
    Jerez A, Sugimoto Y, Makishima H et al. (2012b) Loss of heterozygosity in 7q myeloid disorders: clinical associations and genomic pathogenesis. Blood 119(25): 6109–6117.
    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.
    Kanagal-Shamanna R, Bueso-Ramos CE, Barkoh B et al. (2012) Myeloid neoplasms with isolated isochromosome 17q represent a clinicopathologic entity associated with myelodysplastic/myeloproliferative features, a high risk of leukemic transformation, and wild-type TP53. Cancer 118: 2879–2888.
    Keel SB, Phelps S, Sabo KM et al. (2012) Establishing Rps6 hemizygous mice as a model for studying how ribosomal protein haploinsufficiency impairs erythropoiesis. Experimental Hematology 40: 290–294.
    book Klein RD and Marcucci G (2010) "Familial Acute Myeloid Leukemia (AML) with Mutated CEBPA". In: Pagon RA, Bird TD and Dolan CR et al. (eds) GeneReviews. Seattle, WA: University of Washington.
    Klinakis A, Lobry C, Abdel-Wahab O et al. (2011) A novel tumour-suppressor function for the Notch pathway in myeloid leukaemia. Nature 473: 230–233.
    Ko M, Bandukwala HS, An J et al. (2011) Ten–eleven translocation 2 (TET2) negatively regulates homeostasis and differentiation of hematopoietic stem cells in mice. Proceedings of the National Academy of Sciences of the USA 108: 14566–14571.
    Ko M, Huang Y, Jankowska AM et al. (2012) Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2. Nature 468: 839–843.
    Kumar M, Narla A, Nonami A et al. (2009) Coordinate loss of a microRNA Mir 145 and a protein-coding gene RPS14 cooperate in the pathogenesis of 5q- syndrome. ASH Annual Meeting Abstracts 114: 947
    Lai JL, Preudhomme C, Zandecki M et al. (1995) Myelodysplastic syndromes and acute myeloid leukemia with 17p deletion. An entity characterized by specific dysgranulopoiesis and a high incidence of P53 mutations. Leukemia 9: 370–381.
    Lane SW, Sykes SM, Al-Shahrour F et al. (2010) The Apcmin mouse has altered hematopoietic stem cell function and provides a model for MPD/MDS. Blood 115: 3489–3497.
    Laricchia-Robbio L and Nucifora G (2008) Significant increase of self-renewal in hematopoietic cells after forced expression of EVI1. Blood Cells, Molecules, and Diseases 40: 141–147.
    Laricchia-Robbio L, Fazzina R, Li D et al. (2006) Point mutations in two EVI1 Zn fingers abolish EVI1–GATA1 interaction and allow erythroid differentiation of murine bone marrow cells. Molecular and Cellular Biology 26: 7658–7666.
    Lemonnier F, Couronne L, Parrens M et al. (2012) Recurrent TET2 mutations in peripheral T-cell lymphomas correlate with TFH-like features and adverse clinical parameters. Blood 120(7): 1466–1469.
    Ley TJ, Ding L, Walter MJ et al. (2011) DNMT3A mutations in acute myeloid leukemia. New England Journal of Medicine 363: 2424–2433.
    Li Z, Cai X, Cai CL et al. (2011) Deletion of Tet2 in mice leads to dysregulated hematopoietic stem cells and subsequent development of myeloid malignancies. Blood 118: 4509–4518.
    Liew E and Owen C (2011) Familial myelodysplastic syndromes: a review of the literature. Haematologica 96: 1536–1542.
    List A, Dewald G, Bennett J et al. (2006) Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. New England Journal of Medicine 355: 1456–1465.
    Liu YC, Ito Y, Hsiao HH et al. (2006) Risk factor analysis in myelodysplastic syndrome patients with del(20q): prognosis revisited. Cancer Genetics and Cytogenetics 171: 9–16.
    Liu TX, Becker MW, Jelinek J et al. (2007) Chromosome 5q deletion and epigenetic suppression of the gene encoding alpha-catenin (CTNNA1) in myeloid cell transformation. Nature Medicine 13: 78–83.
    Liu F, Zhao X, Perna F et al. (2011) JAK2V617F-mediated phosphorylation of PRMT5 downregulates its methyltransferase activity and promotes myeloproliferation. Cancer Cell 19: 283–294.
    Loh ML, Sakai DS, Flotho C et al. (2009) Mutations in CBL occur frequently in juvenile myelomonocytic leukemia. Blood 114: 1859–1863.
    Lu C, Ward PS, Kapoor GS et al. (2012) IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483: 474–478.
    Makishima H, Cazzolli H, Szpurka H et al. (2009) Mutations of E3 ubiquitin ligase Cbl family members constitute a novel common pathogenic lesion in myeloid malignancies. Journal of Clinical Oncology 27: 6109–6116.
    Makishima H, Visconte V, Sakaguchi H et al. (2012) Mutations in the spliceosome machinery, a novel and ubiquitous pathway in leukemogenesis. Blood 119: 3203–3210.
    Malcovati L, Papaemmanuil E, Bowen DT et al. (2011) Clinical significance of SF3B1 mutations in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms. Blood 118: 6239–6246.
    Mardis ER, Ding L, Dooling DJ et al. (2009) Recurring Mutations Found by Sequencing an Acute Myeloid Leukemia Genome. New England Journal of Medicine 361: 1058–1066.
    Matheny CJ, Speck ME, Cushing PR et al. (2007) Disease mutations in RUNX1 and RUNX2 create nonfunctional, dominant-negative, or hypomorphic alleles. European Molecular Biology Organization Journal 26: 1163–1175.
    Moran-Crusio K, Reavie L, Shih A et al. (2011) Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation. Cancer Cell 20: 11–24.
    Narla A, Vlachos A and Nathan DG (2011) Diamond Blackfan anemia treatment: past, present, and future. Seminars in Hematology 48: 117–123.
    Nikoloski G, Langemeijer SMC, Kuiper RP et al. (2010) Somatic mutations of the histone methyltransferase gene EZH2 in myelodysplastic syndromes. Nature Genetics 42: 665–667.
    Owen C (2010) Insights into familial platelet disorder with propensity to myeloid malignancy (FPD/AML). Leukemia Research 34: 141–142.
    Papaemmanuil E, Cazzola M, Boultwood J et al. (2011) Somatic SF3B1 mutation in myelodysplasia with ring sideroblasts. New England Journal of Medicine 365: 1384–1395.
    Patel JP, Gonen M, Figueroa ME et al. (2012) Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. New England Journal of Medicine 366: 1079–1089.
    Patnaik MM, Lasho TL, Hodnefield JM et al. (2012a) SF3B1 mutations are prevalent in myelodysplastic syndromes with ring sideroblasts but do not hold independent prognostic value. Blood 119: 569–572.
    Patnaik MM, Hanson CA, Hodnefield JM et al. (2012b) Differential prognostic effect of IDH1 versus IDH2 mutations in myelodysplastic syndromes: a Mayo Clinic study of 277 patients. Leukemia 26: 101–105.
    Pellagatti A, Cazzola M, Giagounidis A et al. (2010) Deregulated gene expression pathways in myelodysplastic syndrome hematopoietic stem cells. Leukemia 24: 756–764.
    Perna F, Gurvich N, Hoya-Arias R et al. (2010) Depletion of L3MBTL1 promotes the erythroid differentiation of human hematopoietic progenitor cells: possible role in 20q- polycythemia vera. Blood 116(15): 2812–2821.
    Poppe B, Dastugue N, Vandesompele J et al. (2006) EVI1 is consistently expressed as principal transcript in common and rare recurrent 3q26 rearrangements. Genes, Chromosomes and Cancer 45: 349–356.
    Quivoron C, Couronne L, Della Valle V et al. (2011) TET2 inactivation results in pleiotropic hematopoietic abnormalities in mouse and is a recurrent event during human lymphomagenesis. Cancer Cell 20: 25–38.
    Ribeiro AF, Pratcorona M, Erpelinck-Verschueren C et al. (2012) Mutant DNMT3A: a new marker of poor prognosis in acute myeloid leukemia. Blood 119: 5824–5831.
    Sanada M, Suzuki T, Shih LY et al. (2009) Gain-of-function of mutated C-CBL tumour suppressor in myeloid neoplasms. Nature 460: 904–908.
    Saur SJ, Sangkhae V, Geddis AE, Kaushansky K and Hitchcock IS (2010) Ubiquitination and degradation of the thrombopoietin receptor c-Mpl. Blood 115(6): 1254–1263.
    Schanz J, Tuchler H, Sole F et al. (2012) New comprehensive cytogenetic scoring system for primary myelodysplastic syndromes (MDS) and oligoblastic acute myeloid leukemia after MDS derived from an international database merge. Journal of Clinical Oncology 30: 820–829.
    Schmitt-Graeff AH, Teo SS, Olschewski M et al. (2008) JAK2V617F mutation status identifies subtypes of refractory anemia with ringed sideroblasts associated with marked thrombocytosis. Haematologica 93: 34–40.
    Sekeres MA (2010) The epidemiology of myelodysplastic syndromes. Hematology/Oncology Clinics of North America 24: 287–294.
    Sloand EM, Pfannes L, Chen G et al. (2007) CD34 cells from patients with trisomy 8 myelodysplastic syndrome (MDS) express early apoptotic markers but avoid programmed cell death by up-regulation of antiapoptotic proteins. Blood 109: 2399–2405.
    Sloand EM, Melenhorst JJ, Tucker ZC et al. (2011) T-cell immune responses to Wilms tumor 1 protein in myelodysplasia responsive to immunosuppressive therapy. Blood 117: 2691–2699.
    Smith ML, Cavenagh JD, Lister TA and Fitzgibbon J (2004) Mutation of CEBPA in familial acute myeloid leukemia. The New England Journal of Medicine 351(23): 2403–2407.
    Smith AE, Mohamedali AM, Kulasekararaj A et al. (2010) Next-generation sequencing of the TET2 gene in 355 MDS and CMML patients reveals low-abundance mutant clones with early origins, but indicates no definite prognostic value. Blood 116: 3923–3932.
    Soderholm J, Kobayashi H, Mathieu C, Rowley JD and Nucifora G (1997) The leukemia-associated gene MDS1/EVI1 is a new type of GATA-binding transactivator. Leukemia 11(3): 352–358.
    Sportoletti P, Grisendi S, Majid SM et al. (2008) Npm1 is a haploinsufficient suppressor of myeloid and lymphoid malignancies in the mouse. Blood 111: 3859–3862.
    Starczynowski DT, Kuchenbauer F, Argiropoulos B et al. (2010) Identification of miR-145 and miR-146a as mediators of the 5q- syndrome phenotype. Nature Medicine 16: 49–58.
    Steensma DP and Tefferi A (2008) JAK2 V617F and ringed sideroblasts: not necessarily RARS-T. Blood 111: 1748.
    Steensma DP, Dewald GW, Lasho TL et al. (2005) The JAK2 V617F activating tyrosine kinase mutation is an infrequent event in both “atypical” myeloproliferative disorders and myelodysplastic syndromes. Blood 106: 1207–1209.
    Stein S, Ott MG, Schultze-Strasser S et al. (2010) Genomic instability and myelodysplasia with monosomy 7 consequent to EVI1 activation after gene therapy for chronic granulomatous disease. Nature Medicine 16: 198–204.
    Tartaglia M, Niemeyer CM, Fragale A et al. (2003) Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nature Genetics 34: 148–150.
    Thiel A, Beier M, Ingenhag D et al. (2011) Comprehensive array CGH of normal karyotype myelodysplastic syndromes reveals hidden recurrent and individual genomic copy number alterations with prognostic relevance. Leukemia 25: 387–399.
    Thol F, Kade S, Schlarmann C et al. (2012b) Frequency and prognostic impact of mutations in SRSF2, U2AF1, and ZRSR2 in patients with myelodysplastic syndromes. Blood 119: 3578–3584.
    Thol F, Yun H, Sonntag AK et al. (2012a) Prognostic significance of combined MN1, ERG, BAALC, and EVI1 (MEBE) expression in patients with myelodysplastic syndromes. Annals of Hematology 91(8): 1221–1233.
    Tiu RV, Gondek LP, O'Keefe CL et al. (2011) Prognostic impact of SNP array karyotyping in myelodysplastic syndromes and related myeloid malignancies. Blood 117: 4552–4560.
    Van den Berghe H, Cassiman JJ, David G et al (1974) Distinct haematological disorder with deletion of long arm of no. 5 chromosome. Nature 251(5474): 437–438.
    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 114: 937–951.
    Vercauteren SM, Starczynowski DT, Sung S et al. (2012) T cells of patients with myelodysplastic syndrome are frequently derived from the malignant clone. British Journal of Haematology 156: 409–412.
    Walter MJ, Ding L, Shen D et al. (2011) Recurrent DNMT3A mutations in patients with myelodysplastic syndromes. Leukemia 25(7): 1153–1158.
    Walter MJ, Shen D, Ding L et al. (2012) Clonal architecture of secondary acute myeloid leukemia. New England Journal of Medicine 366: 1090–1098.
    Wang PW, Eisenbart JD, Espinosa R et al. (2000) 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 67: 28–39.
    Wang J, Fernald AA, Anastasi J , Le Beau MM and Qian Z (2010) Haploinsufficiency of Apc leads to ineffective hematopoiesis. Blood 115: 3481–3488.
    Ward PS, Patel J, Wise DR et al. (2010) The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting [alpha]-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 17: 225–234.
    Watanabe-Okochi N, Kitaura J, Ono R et al. (2008) AML1 mutations induced MDS and MDS/AML in a mouse BMT model. Blood 111: 4297–4308.
    Wattel E, Preudhomme C, Hecquet B et al. (1994) p53 mutations are associated with resistance to chemotherapy and short survival in hematologic malignancies. Blood 84: 3148–3157.
    Wei S, Chen X, Rocha K et al. (2009) A critical role for phosphatase haplodeficiency in the selective suppression of deletion 5q MDS by lenalidomide. Proceedings of the National Academy of Sciences of the USA 106: 12974–12979.
    Wiktor A, Rybicki BA, Piao ZS et al. (2000) Clinical significance of Y chromosome loss in hematologic disease. Genes, Chromosomes and Cancer 27: 11–16.
    Wong AK, Fang B, Zhang L et al. (2008) Loss of the Y chromosome: an age-related or clonal phenomenon in acute myelogenous leukemia/myelodysplastic syndrome? Archives of Pathology and Laboratory Medicine 132: 1329–1332.
    Wong JCY, Zhang Y, Lieuw KH et al. (2010) Use of chromosome engineering to model a segmental deletion of chromosome band 7q22 found in myeloid malignancies. Blood 115: 4524–4532.
    Xu W, Yang H, Liu Y et al. (2011) Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases. Cancer Cell 19: 17–30.
    Ye Y, McDevitt MA, Guo M et al. (2009) Progressive chromatin repression and promoter methylation of CTNNA1 associated with advanced myeloid malignancies. Cancer Research 69: 8482–8490.
    Yoshida K, Sanada M, Shiraishi Y et al. (2011) Frequent pathway mutations of splicing machinery in myelodysplasia. Nature 478: 64–69.
 Further Reading
    Graubert T and Walter MJ (2011) Genetics of myelodysplastic syndromes: new insights. Hematology/the Education Program of the American Society of Hematology 2011: 543–549.
    Odenike O, Anastasi J and Le Beau MM (2011) Myelodysplastic syndromes. Clinics in Laboratory Medicine 31(4): 763–784.

Related Sub-Topics:

Specific Genetic Disorders | Mutational Mechanisms of Genetic Disease | Chromosomal Disorders | Genomic Disorders | Epigenetics and Disease
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Article Title: Molecular Genetics of Myelodysplastic Syndromes
 
How to Cite close
Bejar, Rafael, and Steensma, David P(Nov 2012) Molecular Genetics of Myelodysplastic Syndromes. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0023872]