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

FK228 (romidepsin) and suberoylanilide hydroxamic acid (vorinostat) are histone deacetylase inhibitors (HDACi) approved by the US Food and Drug Administration for cutaneous T-cell lymphoma (CTCL), including the leukemic subtype Se ' zary syndrome. This study investigates RAD23B and STAT3 gene perturbations in a large cohort of primary Se ' zary cells and the effect of FK228 treatment on tyrosine phosphorylation of STAT3 (pYSTAT3) and RAD23B expression. We report RAD23B copy number variation in 10% (12/119, P <= 0.01) of SS patients, associated with reduced mRNA expression (P = 0.04). RAD23B knockdown in a CTCL cell line led to a reduction in FK228-induced apoptosis. Histone deacetylase inhibitor treatment significantly reduced pYSTAT3 in primary Se ' zary cells and was partially mediated by RAD23B. A distinct pattern of RAD23B-pYSTAT3 coexpression in primary Se ' zary cells was detected. Critically, Se ' zary cells harboring the common STAT3 Y640F variant were less sensitive to FK228-induced apoptosis and exogenous expression of STAT3 Y640F, and D661Y conferred partial resistance to STAT3 transcriptional inhibition by FK228 (P <= 0.0024). These findings suggest that RAD23B and STAT3 gene perturbations could reduce sensitivity to histone deacetylase inhibitors in SS patients.