SRSF2 mutations contribute to bone marrow immune microenvironment alterations

Abstract

Somatic SRSF2 mutations are early lesions in myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML), yet how they contribute disease remain unclear. In this study, we generated two murine models that have not yet developed overt MDS/CMML-like phenotypes: (i) a cell-derived xenograft (CDX) by tail-vein injection of stable BA/F3- KRAS G12C - SRSF2 P95H cells and (ii) a Vav1-Cre conditional knock-in mouse heterozygous for Srsf2 P95H . Molecular assays, bulk RNA-seq, and single-cell RNA-seq (scRNA-seq) were used to profile the bone-marrow (BM) microenvironment. CDX mice carrying SRSF2 P95H displayed systemic immune dysregulation. Bulk RNA-seq of Vav1-Cre BM revealed attenuated T cell chemotaxis and elevated immunoglobulin production in Srsf2 P95H/WT animals. Extensive mis-splicing of spliceosomal, epigenetic, and cytoskeletal regulators ( Hnrnpa2b1, Rsrp1, H2az1, Erbin, Akap13 ) was also detected. scRNA-seq demonstrated a reduction in hematopoietic stem and progenitor cells (HSPCs) and an expansion of neutrophil precursors in Srsf2 P95H/WT mice, verifying by flow-cytometry assay. A loss of Natural killer (NK) cells and effector T cells, together with a shift of the B-cell lineage from early precursor states toward more mature and transcriptionally active populations were detected in Srsf2 P95H/WT group, accompanied by enrichment of antibody secretion–related programs. Sanger sequencing confirmed the presence of Srsf2 mutations in this B-cell subset and showed altered expression and alternative splicing of Hnrnpa2b1 , a well-studied target of SRSF2 with P95 mutation. Collectively, these findings suggest that the Srsf2 P95H/WT mutation contributes to the altered hematopoietic lineages composition and immune-related cellular states in BM, providing insights into its potential involvement in early-stage MDS and CMML progression.