title: The oncogenic JUNB/CD30 axis contributes to cell cycle deregulation in ALK+ anaplastic large cell lymphoma.
abstract: 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.
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; First Department of Pathology, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: Vassilis
authors.initials: V
authors.lastname: Atsaves
authors.forename: Lazaros
authors.initials: L
authors.lastname: Lekakis
authors.forename: Elias
authors.initials: E
authors.lastname: Drakos
authors.forename: Vasiliki
authors.initials: V
authors.lastname: Leventaki
authors.forename: Mehran
authors.initials: M
authors.lastname: Ghaderi
authors.forename: George E
authors.initials: GE
authors.lastname: Baltatzis
authors.forename: Dimitris
authors.initials: D
authors.lastname: Chioureas
authors.forename: Dan
authors.initials: D
authors.lastname: Jones
authors.forename: Marianna
authors.initials: M
authors.lastname: Feretzaki
authors.forename: Chryssoula
authors.initials: C
authors.lastname: Liakou
authors.forename: Panayiotis
authors.initials: P
authors.lastname: Panayiotidis
authors.forename: Vassilis
authors.initials: V
authors.lastname: Gorgoulis
authors.forename: Efstratios
authors.initials: E
authors.lastname: Patsouris
authors.forename: L Jeffrey
authors.initials: LJ
authors.lastname: Medeiros
authors.forename: Francois X
authors.initials: FX
authors.lastname: Claret
authors.forename: George Z
authors.initials: GZ
authors.lastname: Rassidakis
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D059447:Cell Cycle Checkpoints; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D018922:HL-60 Cells; D006801:Humans; D017730:Ki-1 Antigen / Q000096:biosynthesis* / Q000235:genetics; D017728:Lymphoma, Large-Cell, Anaplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D000090243:Nucleophosmin; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; C581727:JunB protein, human; D017730:Ki-1 Antigen; C000716967:NPM1 protein, human; D009363:Neoplasm Proteins; D014157:Transcription Factors; D000090243:Nucleophosmin; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases
keywords: CD30; JUNB; anaplastic large cell lymphoma; cell cycle