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

3 Citations (Scopus)

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 - Jan 1 2017
Externally publishedYes

Fingerprint

T-Cell Lymphoma
Retinoids
Cell Cycle
Peripheral T-Cell Lymphoma
Cutaneous T-Cell Lymphoma
Growth
Cyclin-Dependent Kinase 4
Retinoic Acid Receptor alpha
Cyclin-Dependent Kinases
Tretinoin
Transcriptome
Non-Hodgkin's Lymphoma
Cell Differentiation
Transcription Factors
Therapeutics
Down-Regulation
Cell Line
Mutation

Keywords

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

ASJC Scopus subject areas

  • Oncology

Cite this

Retinoic acid receptor alpha drives cell cycle progression and is associated with increased sensitivity to retinoids in T-cell lymphoma. / Wang, Xueju; Dasari, Surendra; Nowakowski, Grzegorz S.; Lazaridis, Konstantinos N.; Wieben, Eric D.; Kadin, Marshall E.; Feldman, Andrew L.; Boddicker, Rebecca L.

In: Oncotarget, Vol. 8, No. 16, 01.01.2017, p. 26245-26255.

Research output: Contribution to journalArticle

Wang, Xueju ; Dasari, Surendra ; Nowakowski, Grzegorz S. ; Lazaridis, Konstantinos N. ; Wieben, Eric D. ; Kadin, Marshall E. ; Feldman, Andrew L. ; Boddicker, Rebecca L. / Retinoic acid receptor alpha drives cell cycle progression and is associated with increased sensitivity to retinoids in T-cell lymphoma. In: Oncotarget. 2017 ; Vol. 8, No. 16. pp. 26245-26255.
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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.",
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AU - Dasari, Surendra

AU - Nowakowski, Grzegorz S.

AU - Lazaridis, Konstantinos N.

AU - Wieben, Eric D.

AU - Kadin, Marshall E.

AU - Feldman, Andrew L.

AU - Boddicker, Rebecca L.

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AB - 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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