Regular Article

contributes toward maintenance of redox balance in CTCL. • Targeting the MUC1-C oncoprotein in CTCL cells induces ROS-mediated death highlighting its potential as an effective strategy. CutaneousT-cell lymphoma(CTCL) is anaggressiveneoplasmwith limited treatments for patients with advanced disease. The mucin 1 C-terminal subunit (MUC1-C) oncoprotein plays a critical role in regulating cell proliferation, apoptosis, and protection from cyto-toxic injury mediated by reactive oxygen species (ROS). Although CTCL cells exhibit re-sistance to ROS-induced apoptosis, the expression and functional significance of MUC1 inCTCLhavenotbeenpreviously investigated.Presentstudiesdemonstrate thatMUC1-C is overexpressed in CTCL cell lines and primaryCTCL cells but is absent in resting T cells from healthy donors and B-cell lymphoma cells. We have developed a cell-penetrating peptide that disrupts homodimerization of the MUC1-C subunit necessary for its nuclear translocation and downstream signaling. We show that treatment of CTCL cells with the MUC1-C inhibitor is associated with downregulation of the p53-inducible regulator of glycolysis and apoptosis and decreases in reduced NAD phosphate and glutathione levels. In concert with these results, targeting MUC1-C in CTCL cells increased ROS and, in turn, inducedROS-mediated late apoptosis/necrosis. TargetingMUC1-C inCTCL tumorxenograftmodelsdemonstratedsignificant decreases indiseaseburden. These findings indicate thatMUC1-Cmaintains redoxbalance inCTCLcells and is thereby anovel target for the treatment of patients with CTCL. (Blood. 2015;126(3):354-362