Sofia Kade

Mutations in genes of the splicing machinery have been described recently in myelodysplastic syndromes (MDS). In the present study, we examined a cohort of 193 MDS patients for mutations in SRSF2, U2AF1 (synonym U2AF35), ZRSR2, and, as described previously, SF3B1, in the context of other molecular markers, including mutations in ASXL1, RUNX1, NRAS, TP53, IDH1, IDH2, NPM1, and DNMT3A. Mutations in SRSF2, U2AF1, ZRSR2, and SF3B1 were found in 24 (12.4%), 14 (7.3%), 6 (3.1%), and 28 (14.5%) patients, respectively, corresponding to a total of 67 of 193 MDS patients (34.7%). SRSF2 mutations were associated with RUNX1 (P < .001) and IDH1 (P = .013) mutations, whereas U2AF1 mutations were associated with ASXL1 (P = .005) and DNMT3A (P = .004) mutations. In univariate analysis, mutated SRSF2 predicted shorter overall survival and more frequent acute myeloid leukemia progression compared with wild-type SRSF2, whereas mutated U2AF1, ZRSR2, and SF3B1 had no impact on patient outcome. In multivariate analysis, SRSF2 remained an independent poor risk marker for overall survival (hazard ratio = 2.3; 95% confidence interval, 1.28-4.13; P = .017) and acute myeloid leukemia progression (hazard ratio = 2.83; 95% confidence interval, 1.31-6.12; P = .008). These results show a negative prognostic impact of SRSF2 mutations in MDS. SRSF2 mutations may become useful for clinical risk stratification and treatment decisions in the future.

Aplastic anemia (AA) is a rare but life-threatening bone marrow failure syndrome; diagnosis is based on cytopenias in peripheral blood and hypocellularity in bone marrow. The distinction between AA and hypocellular myelodysplastic syndrome (MDS) is often difficult to verify, and AA evolves into MDS or AML at a 10-year cumulative incidence of 3.1-9.6%. As AA patients often respond to immunosuppressive therapy, an immune pathophysiology is widely assumed. The evolution of clonal cytogenetic aberrations in hematopoietic cells and the association with clonal paroxysmal nocturnal hemoglobinuria (PNH) suggest that some patients have a clonal hematopoietic disease. Data by Walter and colleagues show that 74% of MDS patients harbor a mutation in at least one of 94 candidate genes, while mutations can still be found in 68% of MDS patients when a core set of 25 genes is analyzed. We hypothesized that mutations that are found in MDS patients may also be present in patients with AA and, therefore, evaluated the mutation profile of 42 genes in AA patients.

MicroRNAs are short (20–40 nucleotides) non-coding RNA molecules that are responsible for the post-transcriptional regulation of gene expression. Aberrant expression of microRNAs has been associated with various malignancies.[1][1],[2][2] Specifically, downregulation of microRNA-142 (miR-142) has