The molecular pathogenesis of the myelodysplastic syndromes

Recent studies have greatly illuminated the genomic landscape of the myelodysplastic syndromes (MDS), and the pace of discovery is accelerating. The most common mutations found in MDS occur in genes involved in RNA splicing (including SF3B1, SRSF2, U2AF1, and ZRSR2) and epigenetic modification (including TET2, ASXL1, and DNMT3A). The identification of spliceosome mutations in approximately half of all patients with MDS implicates abnormalities of RNA splicing, a pathway not previously known as a target for mutation, in the MDS pathogenesis. Several regulators of signal transduction (NRAS, JAK2) and transcription factors (RUNX1, TP53) are also frequently mutated in MDS. The complex patterns of associations between gene mutations identified have revealed epistatic interactions between spliceosome components and epigenetic modifiers in MDS. The cytogenetic abnormalities found in MDS are characterized by the loss of genetic material, whereas translocations are rare. The cytogenetic deletion maps of MDS (e.g., 5q-, 7q-, 20q-) provide us with circumstantial evidence for the presence of tumor suppressor genes. It is now recognized that haploinsufficiency (a gene dosage effect) resulting from gene deletions or inactivating mutations is an important disease mechanism in MDS. Haploinsufficiency of the ribosomal protein gene RPS14 plays a critical role in the development of anemia in the 5q- syndrome, and haploinsufficiency of CUX1 is important in some patients with MDS and AML with complete or partial loss of chromosome 7. Gene expression profiling has identified key deregulated genes and pathways and new prognostic gene signatures in MDS. Recent advances in the molecular pathogenesis of MDS are leading to new biological, clinical, and therapeutic insights.