J Invest Dermatol

Eradication of Sézary Syndrome (SS) is hampered by genetic and molecular heterogeneity. A better understanding of the putative commonalities underlying SS oncogenicity may help to provide more efficient therapies against this disease. The present work analyzes the whole transcriptome of different patient-derived SS cells (n=7) to identify expression patterns and mutational profiles that may provide clues on new therapeutic options for SS patients. Mononuclear cells were recovered by Ficoll gradient from fresh peripheral blood of SS patients (PBMCs). Selected pathway-based inhibitors were used for in vitro drug testing in SS cells using viability assay and flow cytometry (FC). We validated the usefulness of MALT1 inhibitor MI2 using patient-derived SS cells xenografted into eight NSG mice from patient #26. We identified a high variability in the mutational landscape that converge in a restricted number of altered signaling pathways. In vitro data indicated that cell lines and primary malignant SS cells display different sensitivities against pathway inhibitors. MALT1 inhibition, which impacts on NF-κB signaling, led to a robust effect in vitro that was partially reproduced in the NSG model. Our investigations revealed the actual possibility of inhibiting downstream TCR signaling by CARD11, BCL10 and MALT1 in SS therapy.