Dysregulation of the TOX-RUNX3 pathway in cutaneous T-cell lymphoma

Area of Science:

• Immunology
• Molecular Biology
• Dermatology

Background:

• Sézary syndrome (SS) pathogenesis remains largely unknown, hindering diagnosis and treatment.
• The transcription factor TOX plays a role in CD4+ T-cell development and influences RUNX3, a tumor suppressor.
• Identifying key genes in SS pathogenesis is crucial for developing diagnostic and therapeutic strategies.

Purpose of the Study:

• To identify genes involved in Sézary syndrome (SS) pathogenesis.
• To explore the potential of identified genes as diagnostic biomarkers and therapeutic targets for SS.
• To investigate the role of the TOX-RUNX3 pathway in SS.

Main Methods:

• Transcriptome sequencing data analysis to identify candidate genes.
• Quantitative reverse transcription PCR (qRT-PCR) to confirm gene expression levels.
• siRNA-mediated TOX suppression to assess its effect on RUNX3 expression and cell viability.
• Immunohistochemistry to evaluate TOX protein expression in skin biopsies.

Main Results:

• TOX was significantly upregulated (>7 fold) in SS patients (n=5).
• RUNX3 expression was downregulated (0.59 fold), and GATA3 was upregulated (2 fold).
• TOX and RUNX3 expression showed a significant inverse correlation; TOX knockdown rescued RUNX3 expression and reduced cell viability.
• Nuclear TOX protein staining was observed in cutaneous T-cell lymphoma (CTCL) infiltrates in skin biopsies.

Conclusions:

• TOX is upregulated in Sézary syndrome (SS) and inversely proportional to the tumor suppressor RUNX3.
• TOX knockdown demonstrates a functional link to RUNX3 restoration and reduced cell viability.
• TOX protein expression in skin biopsies suggests its potential as a diagnostic biomarker for SS.
• The TOX-RUNX3 pathway warrants further investigation for its role in SS pathogenesis and as a therapeutic target.