Understanding the function of the JunB transcription factor in anaplastic lymphoma kinase-positive, anaplastic large cell lymphoma

Anaplastic lymphoma kinase-positive, anaplastic large cell lymphoma (ALK+ ALCL) is a non-Hodgkin lymphoma thought to arise from an activated T lymphocyte. This lymphoma is characterized by the presence of chromosomal translocations involving the ALK tyrosine kinase, which generate oncogenic fusion proteins, most commonly nucleophosmin (NPM)-ALK. NPM-ALK activates many signalling pathways that drive the proliferation, survival and migration of ALK+ ALCL cells. One of the downstream effectors of NPM-ALK signalling is the activator protein-1 family transcription factor, JunB. JunB is highly expressed in ALK+ ALCL and was reported to promote proliferation of ALK+ ALCL cell lines. Despite this, transcriptional targets of JunB that are important in the pathogenesis of ALK+ ALCL were largely uncharacterized.;To better understand the function of JunB in ALK+ ALCL, we performed a quantitative mass spectrometry screen to identify JunB-regulated proteins in ALK+ ALCL cell lines. We identified the serine protease, Granzyme B (GzB), and the heat shock protein-90 co-chaperone, Cyclophilin 40 (Cyp40), as potential JunB-regulated proteins in ALK+ ALCL. Here, we demonstrate that GzB and Cyp40 are JunB transcriptional targets, and that NPM-ALK and JunB signalling promotes GzB and Cyp40 expression in ALK+ ALCL. By regulating the expression of GzB and the related protein, Perforin, we show that NPM-ALK and JunB influence the cytotoxic phenotype observed in ALK+ ALCL.;Since the expression of GzB and Cyp40 was promoted by oncogenic signalling in ALK+ ALCL, we examined whether they play important roles in the pathogenesis of this lymphoma. Interestingly, we found that GzB expression actually sensitized ALK+ ALCL cell lines to apoptosis following treatment with apoptosis-inducing drugs. This finding is consistent with the observation that ALK+ ALCL patients are often successfully treated using standard chemotherapy regimens. We further found that Cyp40 promoted the viability of ALK+ ALCL cell lines. Together, our results shed light onto the function of an important transcription factor in ALK+ ALCL, and demonstrate that JunB regulates the expression of genes that contribute to multiple aspects of ALK+ ALCL biology. Furthermore, our findings uncover novel signalling events downstream of the NPM-ALK oncoprotein, and better clarify the molecular mechanisms underlying ALK+ ALCL phenotype and pathogenesis.