The oncogenic JUNB/CD30 axis contributes to cell cycle deregulation in ALK+ anaplastic large cell lymphoma
| Autor: | Dan Jones, L. Jeffrey Medeiros, Chryssoula Liakou, Efstratios Patsouris, Elias Drakos, Lazaros Lekakis, Vasiliki Leventaki, George E. Baltatzis, Dimitris Chioureas, George Z. Rassidakis, Marianna Feretzaki, Francois Xavier Claret, Mehran Ghaderi, Panayiotis Panayiotidis, Vassilis Atsaves, Vassilis G. Gorgoulis |
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| Rok vydání: | 2014 |
| Předmět: |
Male
JUNB Cyclin A Ki-1 Antigen Cell Cycle Proteins HL-60 Cells Cyclin D2 hemic and lymphatic diseases medicine Humans Anaplastic lymphoma kinase Anaplastic Lymphoma Kinase Cyclin D3 Anaplastic large-cell lymphoma biology Chemistry Gene Amplification Receptor Protein-Tyrosine Kinases Cell Cycle Checkpoints Hematology Cell cycle medicine.disease Molecular biology Neoplasm Proteins Gene Expression Regulation Neoplastic Cancer research biology.protein Lymphoma Large-Cell Anaplastic Female CDKN1B Nucleophosmin Signal Transduction Transcription Factors |
| Zdroj: | British Journal of Haematology. 167:514-523 |
| ISSN: | 0007-1048 |
| DOI: | 10.1111/bjh.13079 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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