Retinoic acid receptor alpha drives cell cycle progression and is associated with increased sensitivity to retinoids in T-cell lymphoma

// Xueju Wang 1, 2 , Surendra Dasari 3 , Grzegorz S. Nowakowski 4 , Konstantinos N. Lazaridis 5, 6 , Eric D. Wieben 5, 7 , Marshall E. Kadin 8 , Andrew L. Feldman 1, * , Rebecca L. Boddicker 1, * 1 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, United States of America 2 Department of Pathology, China-Japan Union Hospital of Jilin Province, Changchun, Jilin Province, China 3 Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, United States of America 4 Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, United States of America 5 Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, United States of America 6 Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, United States of America 7 Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, United States of America 8 Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Department of Dermatology, Roger Williams Medical Center, Providence, Rhode Island, United States of America * These authors have contributed equally to this work Correspondence to: Andrew L. Feldman, email: feldman.andrew@mayo.edu Rebecca L. Boddicker, email: boddicker.rebecca@mayo.edu Keywords: T-cell lymphoma, retinoids, retinoic acid receptor alpha, all-trans retinoic acid, cell cycle, individualized medicine Received: October 04, 2016 Accepted: February 06, 2017 Published: February 17, 2017 ABSTRACT Peripheral T-cell lymphomas (PTCLs) are aggressive non-Hodgkin lymphomas with generally poor outcomes following standard therapy. Few candidate therapeutic targets have been identified to date. Retinoic acid receptor alpha (RARA) is a transcription factor that modulates cell growth and differentiation in response to retinoids. While retinoids have been used to treat some cutaneous T-cell lymphomas (CTCLs), their mechanism of action and the role of RARA in CTCL and other mature T-cell lymphomas remain poorly understood. After identifying a PTCL with a RARA R394Q mutation, we sought to characterize the role of RARA in T-cell lymphoma cells. Overexpressing wild-type RARA or RARA R394Q significantly increased cell growth in RARA low cell lines, while RARA knockdown induced G1 arrest and decreased expression of cyclin-dependent kinases CDK2/4/6 in RARA high cells. The retinoids, AM80 (tamibarotene) and all- trans retinoic acid, caused dose-dependent growth inhibition, G 1 arrest, and CDK2/4/6 down-regulation. Genes down-regulated in transcriptome data were enriched for cell cycle and G1-S transition. Finally, RARA overexpression augmented chemosensitivity to retinoids. In conclusion, RARA drives cyclin-dependent kinase expression, G 1 -S transition, and cell growth in T-cell lymphoma. Synthetic retinoids inhibit these functions in a dose-dependent fashion and are most effective in cells with high RARA expression, indicating RARA may represent a therapeutic target in some PTCLs.