Cell-autonomous dysregulation of interferon signaling drives clonal expansion of SRSF2-mutant MDS stem/progenitor cells

• SRSF2 mutations blunt responsiveness of MDS cells to IFN stimulation and promote their clonal fitness by downregulating STAT1 expression

• Proteasome inhibition restores STAT1 protein level and sensitivity of SRSF2-mutant MDS cells to IFN, suggesting a new therapeutic strategy

Myelodysplastic syndromes (MDS) are myeloid malignancies often driven by mutations in genes encoding splicing factors (SFs). How these mutations drive the clonal expansion of MDS stem/progenitor cells to outcompete normal hematopoietic stem/progenitor cells (HSPCs) remains unexplained. Although a role for inflammatory processes in promoting clonal expansion of mutant HSPCs and MDS pathogenesis has been proposed, the specific mechanisms implicated remain incompletely understood. In this study, using human isogenic induced pluripotent stem cell (iPSC)-based models of SRSF2-mutant MDS and primary MDS patient cells, we show that the SRSF2 P95L mutation downregulates basal STAT1 expression. STAT1 downregulation dampens interferon (IFN) signaling in MDS stem/progenitor cells, which, unlike normal HSPCs, show resistance to suppression of clonogenic ability by IFNs. Treatment with the proteasome inhibitor bortezomib increased STAT1 protein levels and restored sensitivity of SRSF2-mutant cells to inflammatory stimuli. These results indicate that rewiring of STAT1 signaling by SRSF2 mutations blunts responsiveness to IFNs, conferring clonal fitness to SRSF2-mutant HSPCs against normal HSPCs in the presence of inflammatory stimuli. Our study provides a novel mechanistic link between SF mutations and inflammatory dysregulation and suggests proteasome inhibition as a potential strategy to treat MDS with SRSF2 mutations.