Stress adaptation in splicing factor-mutant myeloid malignancie

Among the most frequently mutated genes in myeloid malignancies, the splicing factors U2AF1 and SRSF2 define molecular subgroups associated with adverse clinical outcomes, highlighting the need to elucidate the mechanisms underlying their aggressive phenotype. Stress granules (SGs) are dynamic ribonucleoprotein condensates enriched in RNA-binding proteinsthat assemble in response to cellular stress and contribute to RNA regulation and stress adaptation. Ina previous study published by our group in 2022, we demonstrated that mutant U2AF1 promotes enhanced stress granule formation in myeloid malignancies, supporting cellular adaptation to stress and increasing mutant cell fitness. Here, we investigated whether disease-associated splicing factor mutations reshape the molecular landscape of stress granules. We isolated SGs from cellular models harboring U2AF1 or SRSF2mutations and performed high-throughput molecular characterization to define their RNA and protein composition. By integrating these datasets, we identified mutation-specific stress granule signatures and uncovered pathways connecting altered RNA processing, stress adaptation, and myeloid diseases pathogenesis. Our findings reveal that splicing factor mutations extend beyond defects in RNA splicing by remodeling stress-responsive ribonucleoprotein condensates, providing new insights into how mutant cells adapt to stress and identifying stress granule-associated pathways as potential therapeutic vulnerabilities in myeloid malignancies.