Silencing Autocrine Death: A Ubiquitin Ligase that Blocks Activation-Induced Cell Death in Cutaneous T-Cell Lymphoma

Cutaneous T-cell lymphoma (CTCL) tumor cells lack the ability of activated T cells to undergo TCR/CD3-mediated activation-induced cell death (AICD). In this issue, the study reported by Wu et al. demonstrates that c-CBL (Casitas B-lineage Lymphoma proto-oncogene) is overexpressed in CTCL. When CTCL cells lose c-CBL, AICD is enhanced. Furthermore, combination therapy with methotrexate (a known demethylating agent for the CD95 gene) in combination with the loss of c-CBL increases CTCL cell death. Therefore, inhibition of c-CBL could represent a method of sensitizing lymphoma cells to enhance AICD. Armed with their novel data, the investigators envision combination therapies that target c-CBL to reactivate AICD in the malignant T cells whenever responsiveness to TCR/CD3 signaling is retained.