Molecular Genetics of Myelodysplastic Syndromes


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. © 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. Copyright © 2011 Massachusetts Medical Society and in the Bejar et al. 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, (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., . 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., . Copyright © 2011 Massachusetts Medical Society.



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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.

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Bejar, Rafael, and Steensma, David P(Nov 2012) Molecular Genetics of Myelodysplastic Syndromes. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0023872]