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ETV6/RUNX1 abrogates mitotic checkpoint function and targets its key player MAD2L1
Oncogene
|March 2, 2010
Summary
The ETV6/RUNX1 (E/R) gene fusion in childhood leukemia may weaken the mitotic checkpoint (MC). This study reveals E/R down-regulates MAD2L1, an MC component, potentially explaining tetraploidy in leukemia cells.
Area of Science:
- Molecular Biology
- Cancer Genetics
- Cell Biology
Background:
- ETV6/RUNX1 (E/R) gene fusion occurs in ~25% of childhood B-cell precursor acute lymphoblastic leukemia.
- This leukemia subtype is linked to specific chromosomal changes like tetraploidy and trisomy 21.
Purpose of the Study:
- To investigate the role of the ETV6/RUNX1 (E/R) fusion gene in mitotic checkpoint (MC) regulation.
- To explore the relationship between E/R, tetraploidy, and the MAD2L1 gene in leukemia.
Main Methods:
- Culturing E/R-expressing Ba/F3 clones and observing karyotype changes.
- Treating E/R-expressing diploid cell lines with spindle toxins to assess mitotic activity.
- Analyzing the regulation of MAD2L1 mRNA and protein by E/R and RUNX1 through promoter binding assays.
Main Results:
- E/R-expressing cells acquired tetraploid karyotypes upon prolonged culture.
- E/R-expressing cells showed reduced 4N DNA content and lower mitotic index when exposed to spindle toxins.
- E/R and RUNX1 down-regulate MAD2L1 expression by binding to RUNX1 sites in the MAD2L1 promoter.
Conclusions:
- ETV6/RUNX1 (E/R) fusion gene attenuates the mitotic checkpoint (MC) by down-regulating MAD2L1.
- This provides a molecular link between E/R, MC dysfunction, and MAD2L1 in leukemia.
- Tetraploidy in E/R-positive leukemia likely requires additional unknown factors for its development.
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