Department of Immunology & Theranostics, Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.
Department of Botany & Plant Sciences, University of California, Riverside, CA 92527, USA.
Sci Adv. 2024 Sep 20;10(38):eado4274. doi: 10.1126/sciadv.ado4274.
Recurrent somatic mutations in spliceosome factor 3b subunit 1 (SF3B1) are identified in hematopoietic malignancies, with SF3B1-K700E being the most common one. Here, we show that regulatory T cell (T)-specific expression of SF3B1-K700E () results in spontaneous autoimmune phenotypes. CD4 T cells from mice display defective T differentiation and inhibitory function, which is demonstrated by failed prevention of adoptive transfer colitis by T. Mechanically, SF3B1-K700E induces an aberrant splicing event that results in reduced expression of a cell proliferation regulator due to the insertion of a 231-base pair DNA fragment to the 5' untranslated region. Forced expression of the gene restores the differentiation and ability of T to prevent adoptive transfer colitis. In addition, acute myeloid leukemia grows faster in aged, but not young, mice compared to mice. Our results highlight the impact of cancer-associated mutation on immune responses, which affect cancer development.
剪接体因子 3b 亚基 1（SF3B1）中的反复体细胞突变在血液系统恶性肿瘤中被鉴定出来，SF3B1-K700E 是最常见的一种。在这里，我们表明 SF3B1-K700E 的调节性 T 细胞（T）特异性表达导致自发性自身免疫表型。来自 小鼠的 CD4 T 细胞显示出缺陷的 T 细胞分化和抑制功能，这可以通过 T 细胞未能预防过继性转移结肠炎来证明。在机制上，SF3B1-K700E 诱导异常剪接事件，导致由于插入到 5'非翻译区的 231 个碱基对 DNA 片段，细胞增殖调节剂 的表达减少。强制表达 基因可恢复 T 的分化和能力，以预防过继转移结肠炎。此外，与 小鼠相比，年龄较大但不是年轻的 小鼠中的急性髓性白血病生长更快。我们的结果强调了与癌症相关的 突变对免疫反应的影响，这会影响癌症的发展。
