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

Xueju Wang, Surendra Dasari, Grzegorz S. Nowakowski, Konstantinos N. Lazaridis, Eric D. Wieben, Marshall E. Kadin, Andrew L. Feldman, Rebecca L. Boddicker

Research output: Contribution to journalArticle

6 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)26245-26255
Number of pages11
JournalOncotarget
Volume8
Issue number16
DOIs
StatePublished - 2017
Externally publishedYes

Keywords

  • All-trans retinoic acid
  • Cell cycle
  • Individualized medicine
  • Retinoic acid receptor alpha
  • Retinoids
  • T-cell lymphoma

ASJC Scopus subject areas

  • Oncology

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