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

Martina Cusan1, Haifeng Shen1, Bo Zhang1,2

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The Journal of Clinical Investigation
|July 18, 2023
PubMed
Summary
This summary is machine-generated.

SF3B1 mutations promote cancer by causing R-loop accumulation, leading to chromosomal instability. Removing these R-loops alleviates this, while ATM deletion worsens it, impacting leukemogenesis.

Keywords:
CancerDNA repairOncology

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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.