2. Academic Validation
  3. Mis-splicing-derived neoantigens and cognate TCRs in splicing factor mutant leukemias

Mis-splicing-derived neoantigens and cognate TCRs in splicing factor mutant leukemias

  • Cell. 2025 Jun 26;188(13):3422-3440.e24. doi: 10.1016/j.cell.2025.03.047.
Won Jun Kim 1,  Edie I Crosse 2,  Emma De Neef 3,  Inaki Etxeberria 4,  Erich Y Sabio 1,  Eric Wang 5,  Jan Philipp Bewersdorf 1,  Kuan-Ting Lin 6,  Sydney X Lu 7,  Andrea Belleville 2,  Nina Fox 1,  Cynthia Castro 1,  Pu Zhang 1,  Takeshi Fujino 1,  Jennifer Lewis 1,  Jahan Rahman 1,  Beatrice Zhang 1,  Jacob H Winick 1,  Alexander M Lewis 1,  Robert F Stanley 1,  Susan DeWolf 1,  Brigita Meškauskaitė Urben 8,  Meril Takizawa 8,  Tobias Krause 8,  Henrik Molina 9,  Ronan Chaligne 8,  Priya Koppikar 10,  Jeffrey Molldrem 10,  Mathieu Gigoux 11,  Taha Merghoub 11,  Anthony Daniyan 1,  Smita S Chandran 4,  Benjamin D Greenbaum 12,  Christopher A Klebanoff 13,  Robert K Bradley 14,  Omar Abdel-Wahab 15
Affiliations

Affiliations

  • 1 Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center (MSK), New York, NY, USA.
  • 2 Public Health Sciences and Basic Sciences Divisions, Fred Hutchinson Cancer Center, Seattle, WA, USA.
  • 3 Public Health Sciences and Basic Sciences Divisions, Fred Hutchinson Cancer Center, Seattle, WA, USA; Department of Genome Sciences, University of Washington, Seattle, WA, USA.
  • 4 Human Oncology and Pathogenesis Program, MSK, New York, NY, USA.
  • 5 The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
  • 6 Codify Therapeutics, Cambridge, MA, USA.
  • 7 Department of Medicine, Division of Hematology, Stanford University, Palo Alto, CA, USA.
  • 8 Single-cell Analytics Innovation Laboratory, MSK, New York, NY, USA.
  • 9 Proteomics Resource Center, Rockefeller University, New York, NY, USA.
  • 10 Department of Hematopoietic Biology and Malignancy, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 11 Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Sandra and Edward Meyer Cancer Center, Weill Cornell Medical Center, New York, NY, USA.
  • 12 Computational Oncology, Department of Epidemiology and Biostatistics, MSK, New York, NY, USA.
  • 13 Human Oncology and Pathogenesis Program, MSK, New York, NY, USA; Parker Institute for Cancer Immunotherapy, New York, NY, USA. Electronic address: klebanoc@mskcc.org.
  • 14 Public Health Sciences and Basic Sciences Divisions, Fred Hutchinson Cancer Center, Seattle, WA, USA; Department of Genome Sciences, University of Washington, Seattle, WA, USA. Electronic address: rbradley@fredhutch.org.
  • 15 Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center (MSK), New York, NY, USA. Electronic address: abdelwao@mskcc.org.
PMID: 40273911 DOI: 10.1016/j.cell.2025.03.047
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.

Keywords

RNA splicing; SF3B1; SRSF2; T cell receptor; U2AF1; ZRSR2; acute myeloid leukemia; immunotherapy; myelodysplastic syndromes; neoantigen.

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