The oncogenic JUNB/CD30 axis contributes to cell cycle deregulation in ALK+ anaplastic large cell lymphoma

Vassilis Atsaves, Lazaros Lekakis, Elias Drakos, Vasiliki Leventaki, Mehran Ghaderi, George E. Baltatzis, Dimitris Chioureas, Dan Jones, Marianna Feretzaki, Chryssoula Liakou, Panayiotis Panayiotidis, Vassilis Gorgoulis, Efstratios Patsouris, L. Jeffrey Medeiros, Francois X. Claret, George Z. Rassidakis

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19 Scopus citations

Abstract

Summary: Anaplastic lymphoma kinase (ALK)+ anaplastic large cell lymphoma (ALCL) frequently carries the t(2;5)(p23;q35) resulting in expression of NPM1(NPM)-ALK oncogenic kinase. The latter is capable of activating ERK kinase, which upregulates JUNB expression through ETS1. JUNB, in turn, interacts with the TNFRSF8 (CD30) gene promoter and induces CD30 (TNFRSF8) overexpression. However, the role of CD30 overexpression in ALK+ ALCL oncogenesis remains unknown. Here we show that the JUNB gene is frequently amplified in ALK+ ALCL, suggesting gene amplification as an additional underlying mechanism for JUNB overexpression. Silencing of JUNB resulted in reduced cell growth and colony formation associated with decreased activator protein-1 activity and G1/S and G2/M cell cycle arrest. These effects were linked to decreased CD30 levels, downregulation of CCNA2 (Cyclin A), CCND2 (Cyclin D2) and CCND3 (Cyclin D3) and upregulation of cyclin-dependent kinase inhibitors CDKN2A (p14) and CDKN1A (p21), but not CDKN1B (p27). Similar cell cycle changes were observed following the knock-down of TNFRSF8 gene or blockade of its function using anti-CD30 antibodies, which were associated with upregulation of CDKN2A and CDKN1A, but not CDKN1B. These findings indicate that JUNB may partly operate through CD30 signalling. Silencing of JUNB also sensitized NPM1-ALCL+ cells to standard chemotherapeutic agents. Our findings uncover the oncogenic role of the JUNB/CD30 axis and its potential as therapeutic target in ALK+ ALCL.

Original languageEnglish (US)
Pages (from-to)514-523
Number of pages10
JournalBritish Journal of Haematology
Volume167
Issue number4
DOIs
StatePublished - Nov 1 2014
Externally publishedYes

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Keywords

  • Anaplastic large cell lymphoma
  • CD30
  • Cell cycle
  • JUNB

ASJC Scopus subject areas

  • Hematology

Cite this

Atsaves, V., Lekakis, L., Drakos, E., Leventaki, V., Ghaderi, M., Baltatzis, G. E., Chioureas, D., Jones, D., Feretzaki, M., Liakou, C., Panayiotidis, P., Gorgoulis, V., Patsouris, E., Medeiros, L. J., Claret, F. X., & Rassidakis, G. Z. (2014). The oncogenic JUNB/CD30 axis contributes to cell cycle deregulation in ALK+ anaplastic large cell lymphoma. British Journal of Haematology, 167(4), 514-523. https://doi.org/10.1111/bjh.13079