Mutations in the RNA splicing factor gene SF3B1 are common across hematologic and solid cancers and result in widespread alterations in splicing, yet there is currently no therapeutic means to correct this mis-splicing. Here, we utilize synthetic introns uniquely responsive to mutant SF3B1 to identify trans factors required for aberrant mutant SF3B1 splicing activity. This revealed the G-patch domain-containing protein GPATCH8 as required for mutant SF3B1-induced splicing alterations and impaired hematopoiesis. GPATCH8 is involved in quality control of branchpoint selection, interacts with the RNA helicase DHX15, and functionally opposes SURP and G-patch domain containing 1 (SUGP1), a G-patch protein recently implicated in SF3B1-mutant diseases. Silencing of GPATCH8 corrected one-third of mutant SF3B1-dependent splicing defects and was sufficient to improve dysfunctional hematopoiesis in SF3B1-mutant mice and primary human progenitors. These data identify GPATCH8 as a novel splicing factor required for mis-splicing by mutant SF3B1 and highlight the therapeutic impact of correcting aberrant splicing in SF3B1-mutant cancers.

RNA剪接因子基因SF3B1的突变在血液癌和实体癌中很常见，并导致剪接的广泛改变，但目前没有治疗方法来纠正这种错误剪接。在这里，我们利用对突变体 SF3B1 独特响应的合成内含子来识别异常突变体 SF3B1 剪接活性所需的反式因子。这揭示了含有 G 补丁结构域的蛋白 GPATCH8，是突变体 SF3B1 诱导的剪接改变和造血受损所必需的。 GPATCH8 参与分支点选择的质量控制，与 RNA 解旋酶 DHX15 相互作用，并在功能上对抗 SURP 和 G-patch 结构域包含 1 (SUGP1)，这是一种最近与SF3B1突变疾病有关的 G-patch 蛋白。 GPATCH8的沉默纠正了三分之一的突变型SF3B1依赖性剪接缺陷，并且足以改善SF3B1突变型小鼠和人类原代祖细胞中功能失调的造血功能。这些数据将 GPATCH8 确定为突变体 SF3B1 错误剪接所需的新型剪接因子，并强调了纠正SF3B1突变体癌症中的异常剪接的治疗影响。