Multiple myeloma subtypes are driven by a variety of genetic abnormalities. Given the genetic diversity of the disease, identification of oncogenic mechanisms common to all subtypes is highly desirable. In a study reported in Cancer Cell, Lamy and colleagues found that that all multiple myeloma lines require caspase-10 for survival irrespective of their genetic abnormalities. This effect of caspase-10, which was unexpectedly discovered during loss-of-function RNA interference screening to identify therapeutic targets in multiple myeloma, occurs through inhibition of autophagic cell death.
The investigators found that the transcription factor IRF4, a master regulator of the plasma cell phenotype found at higher levels in multiple myeloma than in normal plasma cells, induces both caspase-10 and its associated protein cFLIPL in multiple myeloma. This results in a caspase-10/cFLIPL protease that blocks an autophagy-dependent cell death pathway.
In particular, caspase-10 was found to promote survival by cleaving BCLAF1 (BCL2-interacting protein), an inducer of autophagic death that acts by displacing beclin-1 from BCL2. As a result of an as-yet undefined mechanism, multiple myeloma cells preferentially express cFLIPL, which promotes caspase-10 activity, and not the inhibitory cFLIPS isoform.
In the context of this finding, the investigators stated, “Caspase-10 modulates this autophagic response, preventing it from inducing cell death. Therapies targeting caspase-10 would exploit this regulatory pathway and could have broad efficacy across myeloma subtypes.” ■
Lamy L, et al: Cancer Cell 23:435-449, 2013.