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

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

  • Oncotarget. 2017 Apr 18;8(16):26245-26255. doi: 10.18632/oncotarget.15441.
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
Affiliations

Affiliations

  • 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.
PMID: 28412739 DOI: 10.18632/oncotarget.15441
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 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.

Keywords

T-cell lymphoma; all-trans retinoic acid; cell cycle; individualized medicine; retinoic acid receptor alpha; retinoids.

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