1. SF3B1 mutation and ATM deletion codrive leukemogenesis via centromeric R-loop dysregulation
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Cusan, Martina, Shen, Haifeng, Zhang, Bo, Liao, Aijun, Yang, Lu, Jin, Meiling, Fernandez, Mike, Iyer, Prajish, Wu, Yiming, Hart, Kevyn, Gutierrez, Catherine, Nik, Sara, Pruett-Miller, Shondra M., Stark, Jeremy, Obeng, Esther A., Bowman, Teresa V., Wu, Catherine J., Lin, Ren-Jang, and Wang, Lili
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Thermo Fisher Scientific Inc. ,Genes -- Genetic aspects ,B cells -- Genetic aspects ,RNA -- Genetic aspects ,Health care industry - Abstract
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., Introduction Cancer genome sequencing has identified high-frequency mutations of splicing factor SF3B1 in hematologic malignancies such as myelodysplastic syndrome and chronic lymphocytic leukemia (CLL) (1-3). As one of the most [...]
- Published
- 2023
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