Contribution of STAT3 and RAD23B in Primary Sézary Cells to Histone Deacetylase Inhibitor FK228 Resistance

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Cutaneous T-cell lymphoma (CTCL), including Sézary syndrome (SS), is treated with histone deacetylase inhibitors (HDACi).
• RAD23B and STAT3 are key genes implicated in cellular processes and cancer.

Purpose of the Study:

• To investigate RAD23B and STAT3 gene perturbations in primary Sézary cells.
• To determine the effect of FK228 treatment on STAT3 phosphorylation and RAD23B expression in SS.

Main Methods:

• Analysis of RAD23B copy number variation and mRNA expression in 119 SS patients.
• RAD23B knockdown in a CTCL cell line to assess FK228-induced apoptosis.
• Assessment of pYSTAT3 levels and RAD23B-pYSTAT3 co-expression following HDACi treatment.
• Evaluation of STAT3 variants (Y640F, D661Y) for FK228 sensitivity.

Main Results:

• RAD23B copy number variation was found in 10% of SS patients, correlating with reduced mRNA expression.
• RAD23B knockdown decreased FK228-induced apoptosis in a CTCL cell line.
• FK228 treatment reduced pYSTAT3 in primary Sézary cells, partly mediated by RAD23B.
• STAT3 Y640F and D661Y variants conferred partial resistance to FK228 treatment.

Conclusions:

• RAD23B and STAT3 gene alterations are associated with reduced sensitivity to HDAC inhibitors in Sézary syndrome.
• RAD23B and specific STAT3 variants may serve as predictive biomarkers for HDACi therapy in CTCL.