2025年4月23日出版的《细胞》杂志发表了斯隆凯特琳学院Omar Abdel-Wahab团队的最新成果，他们报道了剪接因子突变白血病中的错误剪接衍生新抗原和同源TCR。

课题组人员发现了一系列真正的新抗原，这些新抗原是从新形态的、与白血病相关的体细胞剪接机制突变促进的高度刻板剪接改变中翻译出来的。课题组人员利用特征条形码多肽-主要组织相容性复合体（MHC）右旋聚体从健康供体、活动性髓系恶性肿瘤患者和治疗性异基因干细胞移植后分离新抗原反应性T细胞受体（TCRs）。新抗原反应性CD8⁺ T细胞存在于活动性癌症患者的血液中，并且具有与病毒反应性T细胞不同的表型，具有细胞毒性功能受损的证据。T细胞工程化TCRs识别由CLK3和RHOT2错误剪接事件引起的SRSF2突变诱导的新抗原，导致对SRSF2突变白血病的特异性识别和细胞毒性。这些数据确定了复发性RNA错剪接事件是髓性白血病中可操作的公共新抗原的原因，并为基因重定向T细胞识别这些靶标提供了概念证明。

研究人员表示，RNA剪接因子的突变在癌症中普遍存在，并产生反复剪接错误的mRNA亚型。

附：英文原文

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

Author: Won Jun Kim, Edie I. Crosse, Emma De Neef, Inaki Etxeberria, Erich Y. Sabio, Eric Wang, Jan Philipp Bewersdorf, Kuan-Ting Lin, Sydney X. Lu, Andrea Belleville, Nina Fox, Cynthia Castro, Pu Zhang, Takeshi Fujino, Jennifer Lewis, Jahan Rahman, Beatrice Zhang, Jacob H. Winick, Alexander M. Lewis, Robert F. Stanley, Susan DeWolf, Brigita Mekauskait Urben, Meril Takizawa, Tobias Krause, Henrik Molina, Ronan Chaligne, Priya Koppikar, Jeffrey Molldrem, Mathieu Gigoux, Taha Merghoub, Anthony Daniyan, Smita S. Chandran, Benjamin D. Greenbaum, Christopher A. Klebanoff, Robert K. Bradley, Omar Abdel-Wahab

Issue&Volume: 2025-04-23

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.

DOI: 10.1016/j.cell.2025.03.047

Source: https://www.cell.com/cell/abstract/S0092-8674(25)00399-X