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The genetic basis of phenotypic heterogeneity in myelodysplastic syndromes

Nature Reviews Cancer volume 12, pages 849–859 (2012)Cite this article

Subjects

Key Points

  • Myelodysplastic syndromes (MDS) are a group of diseases that present with the paradox of cytopenia despite a cellular bone marrow. This can be explained by excessive cytokine-mediated intramedullary apoptosis of haematopoietic cells.

  • Emerging biological insights are providing a molecular basis for the phenotypic and clinical heterogeneity of MDS.

  • Defects in ribosomal biogenesis have been associated with both congenital and acquired anaemias. These defects lead to a ribosomal stress response in the cell with an increase in p53 expression, thus providing one molecular explanation for the excessive apoptosis of MDS cells.

  • Abnormal regulation of haematopoiesis by microRNAs (miRNAs) has now been shown to contribute to the pathology of MDS.

  • The importance of epigenetic changes in MDS — initially suspected because of the responsiveness of patients with MDS to demethylating agents — has been molecularly demonstrated through the identification of mutations in genes controlling chromatin methylation and deacetylation.

  • Multiple oncogenes and tumour suppressor genes are mutated, although none has been specifically associated with MDS.

  • Mutations of specific spliceosome genes, either alone or combined with other genetic abnormalities, may be responsible for different MDS phenotypes.

  • An incremental understanding of molecular lesions accounting for clonal expansion in the presence of excessive apoptosis — which is the paradox in MDS — will be the roadmap to improved and targeted therapies.

Abstract

Myelodysplastic syndromes (MDS) are malignant clonal disorders of haematopoietic stem cells and their microenvironment, affecting older individuals (median age ∼70 years). Unique features that are associated with MDS — but which are not necessarily present in every patient with MDS — include excessive apoptosis in maturing clonal cells, a pro-inflammatory bone marrow microenvironment, specific chromosomal abnormalities, abnormal ribosomal protein biogenesis, the presence of uniparental disomy, and mutations affecting genes involved in proliferation, methylation and epigenetic modifications. Although emerging insights establish an association between molecular abnormalities and the phenotypic heterogeneity of MDS, their origin and progression remain enigmatic.

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Figure 1: Incidence and prognosis of common chromosomal abnormalities in MDS.

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Acknowledgements

The authors would like to thank C. Westbrook, D. Steensma and E. Estey for their critical reading of the manuscript and their helpful suggestions.

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Authors and Affiliations

  1. Myelodysplastic Syndromes (MDS) Center, Columbia University Medical Center, Milstein Hospital Building, 6N-435, 177 Fort Washington Avenue, New York, 10032, New York, USA

    Azra Raza & Naomi Galili

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  1. Azra Raza
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  2. Naomi Galili
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Correspondence to Azra Raza.

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Glossary

Cytopenias

Deficiencies of a cellular lineage of the blood.

Hypolobated micromegakaryocytes

Abnormally small platelet-forming cells (megakaryocytes) with a decreased number of nuclear lobes.

Ringed sideroblasts

Erythroblasts containing a ring of mitochondria filled with granules of ferritin around the nucleus.

Thrombocytosis

High platelet counts in the blood.

Spliceosome

A protein complex that is responsible for the excision of non-coding introns in precursor mRNA molecules.

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Raza, A., Galili, N. The genetic basis of phenotypic heterogeneity in myelodysplastic syndromes. Nat Rev Cancer 12, 849–859 (2012). https://doi.org/10.1038/nrc3321

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