In vivo consequences of SAC abrogation. Chronic deregulation of the spindle assembly checkpoint triggers myelosuppression and gastrointestinal atrophy

Interference with microtubule dynamics activates the spindle assembly checkpoint (SAC) to prevent chromosome segregation errors. The SAC induces mitotic arrest by inhibiting the anaphase-promoting complex (APC) via the mitotic checkpoint complex (MCC). The MCC component MAD2 neutralises the critical APC cofactor, CDC20, leading to mitotic arrest. In cancer cell lines, this can promote mitochondrial apoptosis involving pro-apoptotic BCL2 family members, including BH3-only proteins BIM and NOXA, as well as multi-domain proteins BAX and BAK. However, relevance and consequences of apoptosis after SAC perturbation in vivo are unclear. By conditional MAD2 overexpression across tissues, we observed that chronic SAC activation triggers bone marrow aplasia and fatal intestinal atrophy. While myelosuppression was compensated, gastrointestinal atrophy was detrimental. Remarkably, co-deletion of Bim/Bcl2l11, but not Bid, Puma/Bbc3 or Noxa/Pmaip, prevented developing gastrointestinal syndrome, identifying BIM as rate-limiting for apoptosis induction in the gastrointestinal epithelium. In contrast, BCL2 overexpression but none of the BH3-only protein deficiencies tested could mitigate myelosuppression, highlighting tissue and cell type-specific survival dependencies in response to SAC perturbation in vivo.