Unraveling the molecular pathophysiology of myelodysplastic syndromes

J Clin Oncol. 2011 Feb 10;29(5):504-15. doi: 10.1200/JCO.2010.31.1175. Epub 2011 Jan 10.


Somatically acquired genetic abnormalities lead to the salient features that define myelodysplastic syndromes (MDS): clonal hematopoiesis, aberrant differentiation, peripheral cytopenias, and risk of progression to acute myeloid leukemia. Although specific karyotypic abnormalities have been linked to MDS for decades, more recent findings have demonstrated the importance of mutations within individual genes, focal alterations that are not apparent by standard cytogenetics, and aberrant epigenetic regulation of gene expression. The spectrum of genetic abnormalities in MDS implicates a wide range of molecular mechanisms in the pathogenesis of these disorders, including activation of tyrosine kinase signaling, genomic instability, impaired differentiation, altered ribosome function, and changes in the bone marrow microenvironment. Specific alterations present in individual patients with MDS may explain much of the heterogeneity in clinical phenotype associated with this disease and can predict prognosis and response to therapy. Elucidation of the full complement of genetic causes of MDS promises profound insight into the biology of the disease, improved classification and prognostic scoring schemes, and the potential for novel targeted therapies with molecular predictors of response.

Publication types

  • Review

MeSH terms

  • Bone Marrow / physiology
  • Chromosome Aberrations
  • DNA-Binding Proteins / genetics
  • Epigenesis, Genetic
  • Genes, p53
  • Humans
  • Mutation
  • Myelodysplastic Syndromes / etiology
  • Myelodysplastic Syndromes / genetics*
  • Proto-Oncogene Proteins / genetics
  • Repressor Proteins / genetics


  • ASXL1 protein, human
  • DNA-Binding Proteins
  • Proto-Oncogene Proteins
  • Repressor Proteins
  • TET2 protein, human