Mis-splicing-derived neoantigens and cognate TCRs in splicing factor mutant leukemias Journal Article
| Authors: | Kim, W. J.; Crosse, E. I.; De Neef, E.; Etxeberria, I.; Sabio, E. Y.; Wang, E.; Bewersdorf, J. P.; Lin, K. T.; Lu, S. X.; Belleville, A.; Fox, N.; Castro, C.; Zhang, P.; Fujino, T.; Lewis, J.; Rahman, J.; Zhang, B.; Winick, J. H.; Lewis, A. M.; Stanley, R. F.; DeWolf, S.; Urben, B. M.; Takizawa, M.; Krause, T.; Molina, H.; Chaligne, R.; Koppikar, P.; Molldrem, J.; Gigoux, M.; Merghoub, T.; Daniyan, A.; Chandran, S. S.; Greenbaum, B. D.; Klebanoff, C. A.; Bradley, R. K.; Abdel-Wahab, O. |
| Article Title: | Mis-splicing-derived neoantigens and cognate TCRs in splicing factor mutant leukemias |
| 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-major histocompatibility complex (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. © 2025 The Author(s) |
| Keywords: | controlled study; leukemia; unclassified drug; gene mutation; human cell; somatic mutation; exon; allogeneic stem cell transplantation; nonhuman; validation process; cd8+ t lymphocyte; t lymphocyte; mass spectrometry; animal cell; mouse; phenotype; animal tissue; gene expression; bone marrow; interleukin 7; animal experiment; cohort analysis; cytotoxicity; t lymphocyte receptor; antigen; genetic transfection; immunotherapy; gamma interferon; immunogenicity; cd4+ t lymphocyte; western blotting; immunoprecipitation; enzyme linked immunospot assay; hla typing; fluorescence activated cell sorting; bioluminescence; rna splicing; myelodysplastic syndromes; mutant; tumor necrosis factor; myeloid leukemia; t cell receptor; acute myeloid leukemia; proof of concept; human; article; sf3b1; rna sequencing; stereotypy; rna splicing factor; gene set enrichment analysis; srsf2; u2af1; neoantigen; zrsr2; single cell rna seq; allogenic cell; trifluoroacetic acid |
| Journal Title: | Cell |
| Volume: | 188 |
| Issue: | 13 |
| ISSN: | 0092-8674 |
| Publisher: | Cell Press |
| Date Published: | 2025-01-01 |
| Start Page: | 3422 |
| End Page: | 3440.e24 |
| Language: | English |
| DOI: | 10.1016/j.cell.2025.03.047 |
| PUBMED: | 40273911 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work