期刊
JOURNAL OF INVESTIGATIVE DERMATOLOGY
卷 139, 期 9, 页码 1975-+出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jid.2019.03.1130
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资金
- Guy's and St Thomas' Charity Prize PhD Programme in Biomedical and Translation Science
- Department of Health via the National Institute for Health Research comprehensive Biomedical Research Centre
- King's Bioscience Institute at King's College London
- King's College London
- King's College Hospital National Health Service Foundation Trust
- MRC [G0400197] Funding Source: UKRI
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.
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