The molecular basis and clinical significance of genetic mutations identified in myelodysplastic syndromes

Myelodysplastic syndromes (MDS) are a heterogeneous cluster of clonal hematopoietic neoplasms manifested by peripheral cytopenias, lineage dysplasia, and a predisposition to acute myeloid leukemia. The pathophysiology of MDS has not been well illustrated. Nevertheless, studies have implicated the MDS phenotype in a broad spectrum of genetic abnormalities. In addition to the known numerical and structural chromosomal abnormalities, with novel genomic sequencing technologies, approximately 80% of MDS patients have been shown to harbor somatic or acquired gene mutations. The mutations have been found to be related to RNA slicing, transcription regulation, DNA methylation, histone modification, DNA repair/tumor suppressor, signal transduction, and the cohesion complex. The clinical significance of the majority of genetic events has been validated based on a large cohort study that identified mutations as predictors for risk stratification in MDS patients and biomarkers for potential targeted therapies. In this review, we describe all novel key mutations in MDS and their significance in pathophysiology and clinical practice.