Comment on Malcovati et al , page 233 Splicing up the classification of myelodysplasia-----------------------------------------------------------------------------------------------------Jerald Radich

The myelodysplastic syndromes (MDSs) are a heterogeneous group of clonal malignancies characterized by cytopenias arising either de novo or after the genotoxic insult of prior radioor chemotherapy. The morbidity and mortality of MDS stem from the complications of the low blood counts (infection and bleeding), or from progression to acute myeloid leukemia (AML). Alas, there are seemingly more classification schemes than effective therapies. Some classification systems focus on diagnosis using morphologic changes such as dysplasia and blast counts (World Health Organization [WHO]), whereas others focus on prognosis using clinical features such as blasts, cytogenetic karyotype, and extent of cytopenias (International Prognostic Scoring System [IPSS]). In sum, these classification systems allow for a prediction of the outcome. These predictions are not based on therapy, but because there are no great therapies in MDS, this distinction is unfortunately generally a moot point. Similar classification systems in AML have recently incorporated certain mutation of certain genes (eg, FLT3 and NPM1) into schemes historically driven by cytogenetic findings. It would seem likely that similar refinement is on the horizon for MDS, as in the last few years the mutational landscape has been pursued and defined, with the characterization of functional categories of mutations, aswell as the identification of certain genes associated with favorable, and poor, outcomes. Indeed, sequencing of genes established in myeloid malignancies first identified several genes associated with poor outcome in MDS (ASXL1, ETV6, EZH2, RUNX1, and TP53). With next-generation sequencing, these genes and novel genes were discovered. Similar to AML, a small set of mutations accounted for most recurrent mutations, and each patient had an average of,10 mutations, far less than in solid tumors. When clustered into biological pathways, genes involved in cell signaling (NRAS, JAK2), DNA methylation (TET2, DMT3A, IDH1/2), cohesion complex (RAD21), and chromatin regulation (ASXL1, EZH2) were characterized. In addition, 2 groups discovered a new pathway commonly mutated in MDS involved in RNA splicing. RNA splicing is a highly specific activity that allows eukaryotes to create an increased diversity of proteins coded from a limited set of genes via alternative splicing of messenger RNA (mRNA). Mutations in genes involved in the E/A splicing complex, essential in recognizing the 39 splice site of mRNA, were found to occur in.50%ofMDScases,making the splicing the most common pathway mutated in MDS. The splicing pathway appears relatively intact in AML, but is also affected in a subset of chronic myelomonocytic leukemia cases. One of the most commonly mutated is splicing factor 3b, subunit 1 (SF3B1), occurring in roughly 25% of all MDS cases. Curiously, mutations in SF3B1 appear to be predominately in MDS cases involving ringed sideroblasts, especially RARS and RCMD-RS. In this issue, Malcovati et al describe some of the clinical and genetic associations of SF3B1 in MDS cases with ringed sideroblasts. Previous to this publication, this group has done substantial work detailing the role of SF3B1 mutation in MDS. In short, they showed (1) a high prevalence of SF3B1 mutations in MDS cases characterized by ringed sideroblasts (65%), (2) a strong positive predictive value of SF3B1 of 98% for the ringed sideroblast phenotype (regardless of WHO category), and (3) a relatively favorable outcome of patients with the SF3B1 mutation. In the current manuscript, the authors expand our understanding of the role ofSF3B1 in RARS andRCMD-RS. The authors studied