Chronic deregulation of the spindle assembly checkpoint triggers 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 neutralises the critical APC cofactor, CDC20, preventing mitotic exit. In cancer cell lines, this can provoke apoptosis involving pro-apoptotic BCL2 family members BIM and NOXA while BCL2 overexpression blocks mitotic cell death, facilitating SAC adaptation. However, the consequences of apoptosis after SAC perturbation in vivo are unclear. By conditional MAD2 overexpression across tissues in mice, we observed that chronic SAC activation triggers bone marrow aplasia and intestinal atrophy. While myelosuppression was tolerated, gastrointestinal atrophy was detrimental. Remarkably, co-deletion of Bim/Bcl2l11, but not Bid, Puma/Bbc3 or Noxa/Pmaip, prevented developing gastrointestinal syndrome caused by chronic SAC activity, identifying BIM as rate-limiting for mitotic cell death in the gastrointestinal epithelium. In contrast, only 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. * SAC : spindle assembly checkpoint APC/C : Anaphase promoting complex MCC : mitotic checkpoint complex CIN : chromosomal instability KO : knock out OE : overexpression Dox : Doxycycline BM : bone marrow SP : spleen LN : lymph node Thy : Thymus HSPCs : Haematopoietic stem and progenitor cells