Authors
Johannes G Weiss, Paul Y Petermann, Irene Rigato, Michael Lohmüller, Felix Honold, Marina Schapfl, Sarah Spöck, Nadine Kinz, Andréa E Tijhuis, René Wardenaar, Marilú Losito, Floris Foijer, Dario Rizotto, Michael Schubert, Sebastian Herzog, Joel S Riley, Verena Labi, Francesca Finotello, Andreas Villunger
Published in
Science advances. Volume 12. Issue 46. Pages eaef2143. Nov 13, 2026. Epub Nov 13, 2026.
Abstract
Chromosomal instability (CIN) is an established driver of aneuploidy and cell death. Here, we investigate the role of apoptosis as a barrier against CIN-driven aneuploidy in B lymphocytes. We found that impairment of their spindle assembly checkpoint via deletion of Mitotic Arrest Deficient 2-Like 1 or mutation of Monopolar Spindle 1 kinase curtails B cell survival. A CRISPR screen identified intermediates of mitochondrial apoptosis as critical, which we confirmed in vivo by overexpression of a B cell-restricted BCL2 transgene, outperforming loss of P53. Notably, cell death inhibition by BCL2 was insufficient to cause aneuploidy-driven B cell transformation, while loss of P53 strongly synergized with tumors featuring stochastic aneuploidies. In contrast, high cell death rates rapidly select for specific karyotypes, facilitating aneuploid tumor cell survival in Eμ-Myc transgenic mice. Hence, cell death inhibition fails to allow CIN-driven aneuploidies to prevail. In contrast, BCL2-regulated apoptosis selects viable aneuploid tumor karyotypes in the presence of oncogenic MYC, a notion with implications for the clinical use of BCL2-targeting therapies.
PMID:
43024719
Bibliographic data and abstract were imported from PubMed on 14 Nov 2026.
Read full publication at:
Please sign in
to see all details.
Advertisement
Stats
- Recommendations n/a n/a positive of 0 vote(s)
- Views 3
- Comments 0