Diverse transcriptomic and mutational patterns but limited functional pathway alterations in patient-derived Sézary...

Area of Science:

• Oncology
• Immunology
• Genetics

Background:

• Sézary Syndrome (SS) presents significant therapeutic challenges due to its inherent genetic and molecular heterogeneity.
• Understanding common oncogenic pathways is crucial for developing effective SS treatments.

Purpose of the Study:

• To analyze the whole transcriptome of patient-derived SS cells to identify expression patterns and mutational profiles.
• To explore potential new therapeutic strategies for SS by identifying commonalities in oncogenicity.

Main Methods:

• Whole transcriptome analysis of seven patient-derived SS cells.
• In vitro drug testing of pathway-based inhibitors on SS cells using viability assays and flow cytometry.
• Validation of MALT1 inhibitor MI2 in a patient-derived SS cells xenograft mouse model.

Main Results:

• Identified significant variability in mutational landscapes converging on a limited set of altered signaling pathways.
• Demonstrated differential sensitivity of SS cell lines and primary malignant SS cells to pathway inhibitors.
• MALT1 inhibition showed a robust in vitro effect on NF-κB signaling, partially replicated in vivo.

Conclusions:

• MALT1 inhibition targeting NF-κB signaling is a viable therapeutic strategy for Sézary Syndrome.
• Targeting downstream T-cell receptor (TCR) signaling components like CARD11, BCL10, and MALT1 presents a promising avenue for SS therapy.