Chronic spindle assembly checkpoint activation causes myelosuppression and gastrointestinal atrophy

Interference with microtubule dynamics in mitosis 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 neutralizes the critical APC cofactor, CDC20, preventing exit from mitosis. Extended mitotic arrest can promote mitochondrial apoptosis and caspase activation. However, the impact of mitotic cell death on tissue homeostasis in vivo is ill-defined. By conditional MAD2 overexpression, we observe that chronic SAC activation triggers bone marrow aplasia and intestinal atrophy in mice. While myelosuppression can be compensated for, gastrointestinal atrophy is detrimental. Remarkably, deletion of pro-apoptotic Bim/Bcl2l11 prevents gastrointestinal syndrome, while neither loss of Noxa/Pmaip or co-deletion of Bid and Puma/Bbc3 has such a protective effect, identifying BIM as rate-limiting apoptosis effector in mitotic cell death of the gastrointestinal epithelium. In contrast, only overexpression of anti-apoptotic BCL2, but none of the BH3-only protein deficiencies mentioned above, can mitigate myelosuppression. Our findings highlight tissue and cell-type-specific survival dependencies in response to SAC perturbation in vivo. Overexpression of the mitotic checkpoint complex component MAD2 causes myelosuppression and gastrointestinal atrophy due to excessive apoptosis. Loss of pro-apoptotic Bim/Bcl2l11 preserves gut homeostasis but not hematopoiesis, indicating tissue-specific survival dependencies.Systemic overexpression of the mitotic check-point complex component MAD2 causes premature lethality in mice. MAD2 overexpression causes combined myelosuppression and gastrointestinal atrophy. Excess MAD2 causes mitotic arrest and cell death in cycling stem and progenitor cells. Gastrointestinal atrophy, but not myelosuppression, can be prevented by the deletion of pro-apoptotic . Overexpression of the mitotic checkpoint complex component MAD2 causes myelosuppression and gastrointestinal atrophy due to excessive apoptosis. Loss of pro-apoptotic Bim/Bcl2l11 preserves gut homeostasis but not hematopoiesis, indicating tissue-specific survival dependencies.