Mutations in SRSF2 occur in myelodysplastic syndromes (MDS) and MDS/myeloproliferative neoplasms (MPN). SRSF2 mutations cluster at proline 95, with the most frequent mutation being a histidine (P95H) substitution. They undergo positive selection, arise early in the course of disease, and have been identified in age-related clonal hemopoiesis. It is not clear how mutation of SRSF2 modifies hemopoiesis or contributes to the development of myeloid bias or MDS/MPN. Two prior mouse models of Srsf2^P95H mutation have been reported; however, these models do not recapitulate many of the clinical features of SRSF2-mutant disease and relied on bone marrow (BM) transplantation stress to elicit the reported phenotypes. We describe a new conditional murine Srsf2^P95H mutation model, where the P95H mutation is expressed physiologically and heterozygously from its endogenous locus after Cre activation. Using multiple Cre lines, we demonstrate that during native hemopoiesis (ie, no BM transplantation), the Srsf2^P95H mutation needs to occur within the hemopoietic stem-cell-containing populations to promote myelomonocytic bias and expansion with corresponding transcriptional and RNA splicing changes. With age, nontransplanted Srsf2^P95H animals developed a progressive, transplantable disease characterized by myeloid bias, morphological dysplasia, and monocytosis, hallmarks of MDS/MPN in humans. Analysis of cooccurring mutations within the BM demonstrated the acquisition of additional mutations that are recurrent in humans with SRSF2 mutations. The tractable Srsf2^P95H/+ knock-in model we have generated is highly relevant to human disease and will serve to elucidate the effect of SRSF2 mutations on initiation and maintenance of MDS/MPN.

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