biostudies-literatureSt Thomas NNCI NIH HHSNIH HHS76https://www.ebi.ac.uk/biostudies/studies/S-EPMC11763779biostudies-literatureUnknown15(1)Cutaneous T-cell lymphoma (CTCL) is a rare T-cell malignancy characterized by inflamed and painful rash-like skin lesions that may affect large portions of the body's surface. Patients experience recurrent infections due to a compromised skin barrier and generalized immunodeficiency resulting from a dominant Th2 immune phenotype of CTCL cells. Given the role of the unfolded protein response (UPR) in normal and malignant T-cell development, we investigated the impact of UPR-inducing drugs on the viability, transcriptional networks, and Th2 phenotype of CTCL. We found that CTCL cells were >5-fold more sensitive to the proteasome inhibitor bortezomib (Btz) and exhibited a distinct signaling and transcriptional response compared to normal CD4+ cells. The CTCL response was dominated by the induBiomoleculesPharmacological Modulation of the Unfolded Protein Response as a Therapeutic Approach in Cutaneous T-Cell Lymphoma.PMC11763779R01 CA245081R01CA245081Reyes LGolick LDolloff NGChristopher BNRobinson RMChapman EZhu XSt Thomas NfalsePharmacological Modulation of the Unfolded Protein Response as a Therapeutic Approach in Cutaneous T-Cell Lymphoma.Cutaneous T-cell lymphoma (CTCL) is a rare T-cell malignancy characterized by inflamed and painful rash-like skin lesions that may affect large portions of the body's surface. Patients experience recurrent infections due to a compromised skin barrier and generalized immunodeficiency resulting from a dominant Th2 immune phenotype of CTCL cells. Given the role of the unfolded protein response (UPR) in normal and malignant T-cell development, we investigated the impact of UPR-inducing drugs on the viability, transcriptional networks, and Th2 phenotype of CTCL. We found that CTCL cells were >5-fold more sensitive to the proteasome inhibitor bortezomib (Btz) and exhibited a distinct signaling and transcriptional response compared to normal CD4+ cells. The CTCL response was dominated by the indu2025-01-01T00:00:00Z2025 Jan2025-04-18T14:27:55.377Z2025-04-07T00:38:39.242ZS-EPMC117637793985847010.3390/biom15010076