Interpreting new molecular genetics in myelodysplastic syndromes

The myelodysplastic syndromes (MDS) are a clinically and cytogenetically heterogeneous group of clonal diseases characterized by ineffective hematopoiesis, peripheral blood cytopenias, and an increased risk of progression to acute myeloid leukemia. The precise molecular mechanisms behind the development of MDS have remained elusive; however, the distinct sensitivity of this disease to DNA methyltransferase inhibitors and the presence of markedly abnormal epigenetic profiles suggested the existence of an epigenetic mechanism underlying the disease. Recently, the advent of new technologies for the detection of genetic abnormalities has led to the description of a set of novel recurrent mutations in patients with this disease. The majority of these novel mutations have been described in genes encoding different components of the epigenetic machinery, many of which are associated with distinct clinical outcomes. Finally, mutations in mRNA splicing genes have also been described recently in MDS, underscoring the molecular complexity that underlies the development of this heterogeneous disease.