Retinoic acid receptor alpha drives cell cycle progression and is associated with increased sensitivity to retinoids in T-cell lymphoma
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Xueju Wang1,2, Surendra Dasari3, Grzegorz S. Nowakowski4, Konstantinos N. Lazaridis5,6, Eric D. Wieben5,7, Marshall E. Kadin8, Andrew L. Feldman1,*, Rebecca L. Boddicker1,*
1Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, United States of America
2Department of Pathology, China-Japan Union Hospital of Jilin Province, Changchun, Jilin Province, China
3Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, United States of America
4Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, United States of America
5Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, United States of America
6Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, United States of America
7Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, United States of America
8Department 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
Andrew L. Feldman, email: firstname.lastname@example.org
Rebecca L. Boddicker, email: email@example.com
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
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 RARAR394Q mutation, we sought to characterize the role of RARA in T-cell lymphoma cells. Overexpressing wild-type RARA or RARAR394Q significantly increased cell growth in RARAlow cell lines, while RARA knockdown induced G1 arrest and decreased expression of cyclin-dependent kinases CDK2/4/6 in RARAhigh cells. The retinoids, AM80 (tamibarotene) and all-trans retinoic acid, caused dose-dependent growth inhibition, G1 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, G1-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.
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