The SRSF2^P95H splicing factor mutation exerts distinct splicing effects across myelopoiesis that converge upon dysregulated G-CSFR signaling

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Presentation Time: 11:30 AM - 12:45 PM
Poster Board Number: B893
Abstract ID: 5616

Presenting Author:
Abigail L Rich , Graduate Student at Vanderbilt Univ., Vanderbilt Univ. Med. Ctr.

Abstract:

SRSF2^P95H (P95H) splicing factor mutations are initiating genetic lesions in myeloid malignancies. They are associated with myeloid-biased hematopoiesis in mouse models and human disease. Mechanistically, P95H substitutions induce transcriptome-wide alterations in RNA splicing that vary by cell type and genetic background, complicating efforts to understand how P95H drives disease. Efforts to understand P95H mutations focus on splicing in progenitor cell populations, however, to date no studies have investigated this mutation in the mature myeloid cells that comprise >40% of the marrow. We evaluated P95H-associated splicing across myelopoiesis. We subjected promyelocytes, myelocytes, and neutrophils from P95H mice to RNAseq and integrated these data with RNAseq from P95H hematopoietic stem cells and human MDS samples. A cluster-based splicing analysis approach identified cell-type specific splicing with overrepresentation of differentially spliced transcripts involved in myeloid effector function pathways in myelocytes and neutrophils. Missplicing of Csf3r/CSF3R, the granulocyte colony-stimulating factor receptor (GCSFR), was conserved. Notably, P95H mouse bone marrow exhibits impaired activation of GCSFR-dependent pathways (STAT3/5, ERK) that is unique to GCSFR. Overall, these results define P95H-driven alternative splicing as a differentiation-dependent phenomenon and implicate dysregulated GCSFR signaling as conserved feature of P95H-dependent myeloid hematopoiesis.