Jianqiang Wu1, Gary S Wood. 1. Departments of Dermatology, University of Wisconsin, and Veterans Affairs Medical Center, Madison, WI 53715, USA.
Abstract
OBJECTIVE: To explore the relationships among (Fas) promoter methylation, Fas expression, and apoptotic sensitivity in cutaneous T-cell lymphoma (CTCL). DESIGN: Laboratory investigation. SETTING: Dermatology research unit of a university medical center. SAMPLES: Five CTCL lines and Sézary syndrome blood. INTERVENTIONS: Treatment of cells with 5-azacytidine (aza), methotrexate, and interferon alfa-2b. MAIN OUTCOME MEASURES: Fas promoter methylation, Fas expression, and sensitivity to Fas-mediated apoptosis. RESULTS: Fas promoter methylation correlates inversely with the level of Fas transcript, protein, and apoptotic sensitivity in CTCL. Increased DNA methylation also correlates with decreased NFkB (nuclear factor kappa-light chain enhancer of activated B cells) binding to the Fas promoter. All of these relationships were reversed by the DNA-demethylating agent, 5-aza. We found that methotrexate also functions as a DNA-demethylating agent by depleting methyl donors and, together with interferon alfa-2b, upregulates Fas and enhances sensitivity to Fas-mediated apoptosis. CONCLUSIONS: These findings help explain the previously reported impressive responses of patients with advanced CTCL to combination therapy with methotrexate and interferon alfa. They also provide a new rationale for the treatment of CTCL with methotrexate and its use in combination with other agents.
OBJECTIVE: To explore the relationships among (Fas) promoter methylation, Fas expression, and apoptotic sensitivity in cutaneous T-cell lymphoma (CTCL). DESIGN: Laboratory investigation. SETTING: Dermatology research unit of a university medical center. SAMPLES: Five CTCL lines and Sézary syndrome blood. INTERVENTIONS: Treatment of cells with 5-azacytidine (aza), methotrexate, and interferon alfa-2b. MAIN OUTCOME MEASURES: Fas promoter methylation, Fas expression, and sensitivity to Fas-mediated apoptosis. RESULTS:Fas promoter methylation correlates inversely with the level of Fas transcript, protein, and apoptotic sensitivity in CTCL. Increased DNA methylation also correlates with decreased NFkB (nuclear factor kappa-light chain enhancer of activated B cells) binding to the Fas promoter. All of these relationships were reversed by the DNA-demethylating agent, 5-aza. We found that methotrexate also functions as a DNA-demethylating agent by depleting methyl donors and, together with interferon alfa-2b, upregulates Fas and enhances sensitivity to Fas-mediated apoptosis. CONCLUSIONS: These findings help explain the previously reported impressive responses of patients with advanced CTCL to combination therapy with methotrexate and interferon alfa. They also provide a new rationale for the treatment of CTCL with methotrexate and its use in combination with other agents.
Authors: Kun Qu; Lisa C Zaba; Ansuman T Satpathy; Paul G Giresi; Rui Li; Yonghao Jin; Randall Armstrong; Chen Jin; Nathalie Schmitt; Ziba Rahbar; Hideki Ueno; William J Greenleaf; Youn H Kim; Howard Y Chang Journal: Cancer Cell Date: 2017-06-15 Impact factor: 31.743