Fig. 6. Schematic overview of the susceptibility of SF3B1^K700E-mutated cells to BV-6-induced cytotoxicity, along with the signalling pathways involved.

(1) The bivalent SMAC mimetic, BV-6, serves as a dual cIAP1 and XIAP inhibitor. (2) BV-6 causes cIAP1 to auto-ubiquitinate thereby targeting cIAP1 for proteasomal degradation. (3) Loss of cIAP1 promotes non-canonical NF-κB signalling and upregulation of NF-κB target genes including TNF. (4) This may promote death receptor signalling through autocrine production of death receptor ligands such as TNF-α (5) Disruption of RIP(K1) ubiquitination promotes the formation of cytosolic TNF Complex II that (6) activates downstream executioner caspases-3/7. (5) Reduced levels of the endogenous caspase-8 inhibitor, cFLIP, in SF3B1^K700E cells further promote caspase-8 activation within TNF Complex II, enabling proteolytic cleavage of BID. (7) The resulting truncated BID (tBID) can then be bound and sequestered by pro-survival proteins (e.g., BCL-2, BCL-X_L, and MCL-1), however, when these pro-survival proteins are saturated or absent, (8) as is the case for BCL-2 levels in SF3B1^K700E cells, tBID and other pro-apoptotic factors can promote mitochondrial outer membrane permeabilisation (MOMP) and the release of apoptogenic factors. In conjunction with (9) BV-6-mediated inhibition of XIAP, this leads to enhanced activation of the mitochondrial (intrinsic) pathway that, in turn, (10) activates downstream executioner caspases-3/7 and culminates in RIP(K1)-dependent apoptosis. ^*P < 0.05; ^**P < 0.01; ***P < 0.001; ^****P < 0.0001.