Schematic representation of ER stress-triggered pathways in B-CLL cells, as potential therapeutic targets. ER stress induces activation of the ER membrane-resident caspase-4, which in turn activates caspase-8 and caspase-3, triggering a novel caspase pathway that leads to spontaneous B-CLL cell apoptosis. Caspase-8 connects ER and mitochondria. Indeed, it cleaves the ER membrane-embedded protein Bap31 into Bap20 and is involved in the release of cytochrome c from mitochondria into the cytosol. Caspase-8–driven cytochrome c release is accompanied by the Bax translocation from cytosol to mitochondria, but whether this latter event is caused by Bap20-dependent mechanisms remains to be elucidated (“?”). Cytochrome c release induces activation of caspase-9, which in turn contributes to cleave caspase-8 and, to a lesser extent (broken line), caspase-3. These results suggest that mitochondria-driven caspase-9 activation, converging on caspase-8, induces an amplification of the ER-triggered caspase cascade rather than an efficient mitochondrial pathway. Moreover, ER stress triggers increased expression of CHOP/GADD153, which also contributes to B-CLL cell apoptosis, and BiP/GRP78, which, on the contrary, triggers antiapoptotic signals in B-CLL cells. Both genetic and pharmacologic interventions increase B-CLL cell apoptosis. The star symbols indicate molecular targets for gene silencing (2 stars) and tunicamycin treatment (one star).