Department of Systems Biology, Beckman Research Institute of the City of Hope, Monrovia, California, USA.
Department of Hematology, Union Hospital Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
J Clin Invest. 2023 Sep 1;133(17):e163325. doi: 10.1172/JCI163325.
RNA splicing factor SF3B1 is recurrently mutated in various cancers, particularly in hematologic malignancies. We previously reported that coexpression of Sf3b1 mutation and Atm deletion in B cells, but not either lesion alone, leads to the onset of chronic lymphocytic leukemia (CLL) with CLL cells harboring chromosome amplification. However, the exact role of Sf3b1 mutation and Atm deletion in chromosomal instability (CIN) remains unclear. Here, we demonstrated that SF3B1 mutation promotes centromeric R-loop (cen-R-loop) accumulation, leading to increased chromosome oscillation, impaired chromosome segregation, altered spindle architecture, and aneuploidy, which could be alleviated by removal of cen-R-loop and exaggerated by deletion of ATM. Aberrant splicing of key genes involved in R-loop processing underlay augmentation of cen-R-loop, as overexpression of the normal isoform, but not the altered form, mitigated mitotic stress in SF3B1-mutant cells. Our study identifies a critical role of splice variants in linking RNA splicing dysregulation and CIN and highlights cen-R-loop augmentation as a key mechanism for leukemogenesis.
RNA 剪接因子 SF3B1 在各种癌症中经常发生突变，特别是在血液恶性肿瘤中。我们之前曾报道，在 B 细胞中共同表达 Sf3b1 突变和 Atm 缺失，但不是单独的任何一种病变，会导致慢性淋巴细胞白血病 (CLL) 的发生，而 CLL 细胞具有染色体扩增。然而，Sf3b1 突变和 Atm 缺失在染色体不稳定性 (CIN) 中的确切作用仍不清楚。在这里，我们证明了 SF3B1 突变促进着丝粒 R 环 (cen-R-loop) 的积累，导致染色体振荡增加、染色体分离受损、纺锤体结构改变和非整倍体，这些可以通过去除 cen-R-loop 得到缓解，并且通过删除 ATM 而被夸大。关键基因的异常剪接参与了 R 环处理，增强了 cen-R-loop，而过表达正常异构体，而不是改变形式，减轻了 SF3B1 突变细胞的有丝分裂应激。我们的研究确定了剪接变体在将 RNA 剪接失调与 CIN 联系起来的关键作用，并强调了 cen-R-loop 的增强是白血病发生的关键机制。
