Aneuploidy impairs B cell development but accelerates their MYC-driven transformation

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 E μ -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.