The oncogenic JUNB / CD 30 axis contributes to cell cycle deregulation in ALK + anaplastic large cell lymphoma

Anaplastic lymphoma kinase ( ALK )+ anaplastic large cell lymphoma ( ALCL ) frequently carries the t(2;5)(p23;q35) resulting in expression of NPM 1( NPM )‐ ALK oncogenic kinase. The latter is capable of activating ERK kinase, which upregulates JUNB expression through ETS 1 . JUNB , in turn, interacts with the TNFRSF 8 ( CD 30 ) gene promoter and induces CD 30 ( TNFRSF 8) overexpression. However, the role of CD 30 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 CD 30 levels, downregulation of CCNA 2 (Cyclin A), CCND 2 (Cyclin D2) and CCND 3 (Cyclin D3) and upregulation of cyclin‐dependent kinase inhibitors CDKN 2A (p14) and CDKN 1A (p21), but not CDKN 1B (p27). Similar cell cycle changes were observed following the knock‐down of TNFRSF 8 gene or blockade of its function using anti‐ CD 30 antibodies, which were associated with upregulation of CDKN 2A and CDKN 1A, but not CDKN 1B. These findings indicate that JUNB may partly operate through CD 30 signalling. Silencing of JUNB also sensitized NPM 1‐ ALCL + cells to standard chemotherapeutic agents. Our findings uncover the oncogenic role of the JUNB / CD 30 axis and its potential as therapeutic target in ALK + ALCL .