TY - JOUR
T1 - SF3B1 mutation and ATM deletion codrive leukemogenesis via centromeric R-loop dysregulation
AU - Cusan, Martina
AU - Shen, Haifeng
AU - Zhang, Bo
AU - Liao, Aijun
AU - Yang, Lu
AU - Jin, Meiling
AU - Fernandez, Mike
AU - Iyer, Prajish
AU - Wu, Yiming
AU - Hart, Kevyn
AU - Gutierrez, Catherine
AU - Nik, Sara
AU - Pruett-Miller, Shondra M.
AU - Stark, Jeremy
AU - Obeng, Esther A.
AU - Bowman, Teresa V.
AU - Wu, Catherine J.
AU - Lin, Ren Jang
AU - Wang, Lili
N1 - Publisher Copyright:
© 2023, Cusan et al.
PY - 2023/9/1
Y1 - 2023/9/1
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI163325
DO - 10.1172/JCI163325
M3 - Article
C2 - 37463047
AN - SCOPUS:85169504521
SN - 0021-9738
VL - 133
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 17
M1 - e163325
ER -