We 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. © 2013 Elsevier Inc.
Lamy, L., Ngo, V. N., Emre, N. C. T., Shaffer, A. L., Yang, Y., Tian, E., … Staudt, L. M. (2013). Control of autophagic cell death by caspase-10 in multiple myeloma. Cancer Cell, 23(4), 435–449. https://doi.org/10.1016/j.ccr.2013.02.017