Faculty, Staff and Student Publications

Language

English

Publication Date

6-26-2025

Journal

Cell

DOI

10.1016/j.cell.2025.03.047

PMID

40273911

PMCID

PMC12204805

PubMedCentral® Posted Date

6-26-2026

PubMedCentral® Full Text Version

Author MSS

Abstract

Mutations in RNA splicing factors are prevalent across cancers and generate recurrently mis-spliced mRNA isoforms. Here we identified a series of bona fide neoantigens translated from highly stereotyped splicing alterations promoted by neomorphic, leukemia-associated somatic splicing machinery mutations. We utilized feature-barcoded peptide-MHC dextramers to isolate neoantigen-reactive T cell receptors (TCRs) from healthy donors, patients with active myeloid malignancy, and following curative allogeneic stem cell transplant. Neoantigen-reactive CD8+ T cells were present in the blood of patients with active cancer and had a distinct phenotype from virus-reactive T cells with evidence of impaired cytotoxic function. T cells engineered with TCRs recognizing SRSF2 mutant-induced neoantigens arising from mis-splicing events in CLK3 and RHOT2 resulted in specific recognition and cytotoxicity of SRSF2-mutant leukemia. These data identify recurrent RNA mis-splicing events as sources of actionable public neoantigens in myeloid leukemias and provide proof-of-concept for genetically redirecting T cells to recognize these targets.

Keywords

Humans, Serine-Arginine Splicing Factors, Receptors, Antigen, T-Cell, Mutation, RNA Splicing, CD8-Positive T-Lymphocytes, Antigens, Neoplasm, RNA Splicing Factors, Leukemia, Acute myeloid leukemia, adoptive cell therapy, immunotherapy, myelodysplastic syndromes, neoantigen, RNA splicing, T cell receptor, SF3B1, SRSF2, U2AF1, ZRSR2

Published Open-Access

yes

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