Control of Autophagic Cell Death by Caspase-10 in Multiple Myeloma

SummaryWe performed a loss-of-function RNA interference screen to define therapeutic targets in multiple myeloma, a genetically diverse plasma cell malignancy. Unexpectedly, we discovered that all myeloma lines require caspase-10 for survival irrespective of their genetic abnormalities. The transcription factor IRF4 induces both caspase-10 and its associated protein cFLIPL in myeloma, generating a protease that does not induce apoptosis but rather blocks an autophagy-dependent cell death pathway. Caspase-10 inhibits autophagy by cleaving the BCL2-interacting protein BCLAF1, itself a strong inducer of autophagy that acts by displacing beclin-1 from BCL2. While myeloma cells require a basal level of autophagy for survival, caspase-10 tempers this response to avoid cell death. Drugs that disrupt this vital balance may have therapeutic potential in myeloma.

► Caspase-10 activity maintains myeloma cell survival
► cFLIP drives caspase-10 activation in multiple myeloma
► Caspase-10 blocks autophagic cell death in myeloma
► Caspase-10 promotes survival by cleaving BCLAF1, an inducer of autophagic death