ZRSR2 Mutations Cause Dysregulated RNA Splicing in MDS

Recurrent somatic mutations have been uncovered in several components of the spliceosome in Myelodysplastic Syndrome (MDS). Recent high throughput sequencing of large cohorts of MDS has established RNA splicing as the pathway most frequently targeted by somatic mutations. These findings implicate dysregulated RNA splicing in the pathogenesis of MDS. However, the mechanism linking aberrant splicing to the development of MDS is unknown. ZRSR2, a frequently mutated spliceosome gene in MDS is located on the X chromosome. Somatic alterations of ZRSR2 are typically inactivating mutations (frameshift indels, nonsense point mutations or splice site mutations) which are observed predominantly in males. Mutations in ZRSR2are more prevalent in MDS subtypes without ring sideroblasts and chronic myelomonocytic leukemia (CMML) and are associated with elevated bone marrow blasts and higher rate of progression to AML. Although ZRSR2 has been suggested to interact with other splice proteins, U2AF2 and SRSF2, at the 3΄ splice sites during the pre-spliceosome assembly, its precise role in RNA splicing remains unexplored.