SF3B1 mutation and ATM deletion codrive leukemogenesis via centromeric R-loop dysregulation

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• SF3B1 mutations are common in hematologic malignancies.
• SF3B1 and ATM alterations cooperate in chronic lymphocytic leukemia (CLL) development.
• The role of SF3B1 mutations and ATM deletion in chromosomal instability (CIN) is not fully understood.

Purpose of the Study:

• To elucidate the role of SF3B1 mutations and ATM deletion in CIN.
• To investigate the mechanism linking RNA splicing dysregulation to CIN.
• To identify key factors in SF3B1-driven leukemogenesis.

Main Methods:

• Assessing the impact of SF3B1 mutation on R-loop formation and chromosome segregation.
• Analyzing chromosome oscillation, spindle architecture, and aneuploidy in SF3B1-mutant cells.
• Evaluating the effect of ATM deletion and R-loop removal on CIN.

Main Results:

• SF3B1 mutation enhances centromeric R-loop (cen-R-loop) accumulation, causing chromosome oscillation, segregation errors, and aneuploidy.
• ATM deletion exacerbates SF3B1-induced CIN, while R-loop removal mitigates it.
• Aberrant splicing of R-loop processing genes contributes to cen-R-loop buildup and mitotic stress in SF3B1-mutant cells.

Conclusions:

• SF3B1 mutation-induced cen-R-loop accumulation is a critical driver of CIN in leukemogenesis.
• RNA splicing defects are linked to CIN through R-loop augmentation.
• Targeting cen-R-loops may offer therapeutic strategies for SF3B1-mutant cancers.