Prostate cancer (PCa) is the most prevalent cancer in men. Hyperactive STAT3 is thought to be oncogenic in PCa. However, targeting of the IL-6/STAT3 axis in PCa patients has failed to provide therapeutic benefit. Here we show that genetic inactivation of Stat3 or IL-6 signalling in a Pten-deficient PCa mouse model accelerates cancer progression leading to metastasis. Mechanistically, we identify p19ARF as a direct Stat3 target. Loss of Stat3 signalling disrupts the ARF–Mdm2–p53 tumour suppressor axis bypassing senescence. Strikingly, we also identify STAT3 and CDKN2A mutations in primary human PCa. STAT3 and CDKN2A deletions co-occurred with high frequency in PCa metastases. In accordance, loss of STAT3 and p14ARF expression in patient tumours correlates with increased risk of disease recurrence and metastatic PCa. Thus, STAT3 and ARF may be prognostic markers to stratify high from low risk PCa patients. Our findings challenge the current discussion on therapeutic benefit or risk of IL-6/STAT3 inhibition.

Aberrant anaplastic lymphoma kinase (ALK) expression is a defining feature of many human cancers and was identified first in anaplastic large-cell lymphoma (ALCL), an aggressive non-Hodgkin T-cell lymphoma. Since that time, many studies have set out to identify the mechanisms used by aberrant ALK toward tumorigenesis. We have identified a distinct profile of micro-RNAs (miRNAs) that characterize ALCL; furthermore, this profile distinguishes ALK + from ALK − subtypes, and thus points toward potential mechanisms of tumorigenesis induced by aberrant ALK. Using a nucleophosmin-ALK transgenic mouse model as well as human primary ALCL tumor tissues and human ALCL-derived cell lines, we reveal a set of overlapping deregulated miRNAs that might be implicated in the development and progression of ALCL. Importantly, ALK + and ALK − ALCL could be distinguished by a distinct profile of "oncomirs": Five members of the miR-17-92 cluster were expressed more highly in ALK + ALCL, whereas miR-155 was expressed more than 10-fold higher in ALK − ALCL. Moreover, miR-101 was down-regulated in all ALCL model systems, but its forced expression attenuated cell proliferation only in ALK + and not in ALK − cell lines, perhaps suggesting different modes of ALK-dependent regulation of its target proteins. Furthermore, inhibition of mTOR, which is targeted by miR-101, led to reduced tumor growth in engrafted ALCL mouse models. In addition to future therapeutical and diagnostic applications, it will be of interest to study the physiological implications and prognostic value of the identified miRNA profiles.micro-RNA | mTOR | miR-155 | miR-101

Bcr-Abl causes chronic myelogenous leukemia, a myeloproliferative disorder characterized by clonal expansion of hematopoietic progenitor cells. In this study, inducible expression of Bcr-Abl in TonB.210 cells is associated with increased production of intracellular reactive oxygen species (ROS), which is thought to play a role in survival signaling when generated at specific levels. Elevated ROS in Bcr-Abl-expressing cells were found to activate PI3k/Akt pathway members such as Akt and GSK3b as well as downstream targets b-catenin and Mcl-1. The activation of these proteins was inhibited by the flavoprotein inhibitor diphenyleneiodonium, which is commonly used to inhibit NADPH oxidase (Nox). This indicated that increased ROS might be related to increased activity of one member of the Nox family. Knock-down experiments using siRNA suggest that Nox-4 is the main source of increased ROS following Bcr-Abl expression. We showed that Bcr-Abl-induced ROS could also increase survival pathway signaling through redox inhibition of PP1a, a serine threonine phosphatase that negatively regulates the PI3k/Akt pathway. Overall our results demonstrate that Bcr-Abl expression increases Nox-4-generated ROS, which in turn increases survival signaling through PI3k/Akt pathway by inhibition of PP1a, thus contributing to the high level of resistance to apoptosis seen in these Bcr-Abl-expressing cells.

Anaplastic Large Cell Lymphoma (ALCL) is a Non-Hodgkin lymphoma found in children and young adults with poor survival rates. ALCLs frequently carry a chromosomal translocation that results in expression of the oncoprotein nucleophosmin-anaplastic lymphoma kinase (NPM-ALK). The key molecular downstream events required for NPM-ALK triggered lymphoma growth are still not entirely clear. Here we show that the AP-1 proteins cJun and JunB promote lymphoma development and tumor dissemination in a murine NPM-ALK lymphomagenesis model via transcriptional regulation of PDGFRB. Therapeutic inhibition of PDGFRB markedly prolonged survival of NPM-ALK transgenic mice and increased the efficacy of an ALK-specific inhibitor in transplanted NPM-ALK tumors. Remarkably, inhibition of PDGFRs in a late stage patient with refractory NPM-ALK-positive ALCL resulted in complete and sustained remission within 10 days of treatment. Our data identify PDGFRB as novel cJun/JunB target that could be utilized for a highly effective therapy to cure ALCL. 3ALCLs are T-cell lymphomas 1,2 that comprise 10-20% of all Non-Hodgkin's lymphoma cases in children and 3% in adults 3 . About half of ALCL cases are positive for NPM-ALK fusion proteins caused by t(2;5)(p23;q35) translocation 4 . ALK translocations or point mutations have also been described in DLBCLs (diffuse large B-cell lymphomas) and in several nonlymphoid neoplasms [5][6][7][8] . Inhibition of ALK fusion proteins by specific compounds such as crizotinib showed promising clinical responses in ALCL and NSCLC (non-small cell lung cancer) 9,10 . However, ALK mutations conferring resistance to crizotinib have also been reported 11 .Recent studies have linked NPM-ALK expression to induction of AP-1 transcription factors JunB and cJun 12,13 . To investigate their role in NPM-ALK-driven T-cell lymphomas, we conditionally deleted cJun and/or JunB in T-cells of transgenic mice carrying the human NPM-ALK fusion-tyrosine-kinase under the control of the murine CD4-promotor 14 (CD4-NPM-ALK) (Fig. 1a). Gene deletion was confirmed by DNA genotyping (data not shown), real-time PCR, Western blotting and immunohistochemistry (IHC) (Suppl. (Fig.1b), however, inactivation of both, cJun and JunB, in CD4-NPM-ALK-CD4 ΔΔJun mice resulted in significantly prolonged survival (Fig. 1b). CD4-NPM-ALK-CD4 ΔΔJun lymphomas showed markedly reduced proliferation and significantly increased apoptosis when compared to CD4-NPM-ALK lymphomas ( Fig. 1c; Suppl. Fig. S2a,b). Consistently, (Fig. 2d) suggesting a transcriptional regulation of PDGFRB by Jun proteins. Consistently, AP-1 consensus sequences were identified within the murine PDGFRB promoter and first intron that were conserved among other species (Suppl. Fig. S3b,c) 15,16 . Moreover, analysis of ENCODE transcription factor binding tracks revealed binding of cJun and JunB to the PDGFRB intronic AP-1 site in the human K562 leukemia cell line (Suppl. Fig. S3d) 15,17 . CD4-NPM-ALK-CD4EMSA analysis of nuclear extracts from NPM-ALK lymphomas demonstrated AP-1 DNA ...

Neuroblastoma (NB) is the most common and deadly solid tumour in children. Despite the development of new treatment options for high-risk NB, over half of patients relapse and five-year survival remains at 40–50%. Therefore, novel treatment strategies aimed at providing long-term disease remission are urgently sought. ALK, encoding the anaplastic lymphoma kinase receptor, is altered by gain-of-function point mutations in around 14% of high-risk NB and represents an ideal therapeutic target given its low or absent expression in healthy tissue postnatally. Small-molecule inhibitors of Anaplastic Lymphoma Kinase (ALK) approved in ALK fusion-positive lung cancer are currently undergoing clinical assessment in patients with ALK-mutant NB. Parallel pre-clinical studies are demonstrating the efficacy of ALK inhibitors against common ALK variants in NB; however, a complex picture of therapeutic resistance is emerging. It is anticipated that long-term use of these compounds will require combinatorial targeting of pathways downstream of ALK, functionally-related ‘bypass’ mechanisms and concomitant oncogenic pathways.

The Activator Protein-1 (AP-1) transcription factor (TF) family, composed of a variety of members including c-JUN, c-FOS and ATF, is involved in mediating many biological processes such as proliferation, differentiation and cell death. Since their discovery, the role of AP-1 TFs in cancer development has been extensively analysed. Multiple in vitro and in vivo studies have highlighted the complexity of these TFs, mainly due to their cell-type specific homo- or hetero-dimerization resulting in diverse transcriptional response profiles. However, as a result of the increasing knowledge of the role of AP-1 TFs in disease, these TFs are being recognized as promising therapeutic targets for various malignancies. In this review, we focus on the impact of deregulated expression of AP-1 TFs in CD30-positive lymphomas including Classical Hodgkin Lymphoma and Anaplastic Large Cell Lymphoma.

BIA-ALCL is a rare neoplasm with a good prognosis. Our data support the recommendation that stage I disease be managed with surgery alone. Adjuvant chemotherapy may be required for more invasive disease and our experience has shown the efficacy of Brentuximab as a second line treatment.

Anaplastic Lymphoma Kinase (ALK)-positive Anaplastic Large Cell Lymphoma (ALCL), remains one of the most curable cancers in the paediatric setting; multi-agent chemotherapy cures approximately 65–90% of patients. Over the last two decades, major efforts have focused on improving the survival rate by intensification of combination chemotherapy regimens and employing stem cell transplantation for chemotherapy-resistant patients. More recently, several new and ‘renewed’ agents have offered the opportunity for a change in the paradigm for the management of both chemo-sensitive and chemo-resistant forms of ALCL. The development of ALK inhibitors following the identification of the EML4-ALK fusion gene in Non-Small Cell Lung Cancer (NSCLC) has opened new possibilities for ALK-positive ALCL. The uniform expression of CD30 on the cell surface of ALCL has given the opportunity for anti-CD30 antibody therapy. The re-evaluation of vinblastine, which has shown remarkable activity as a single agent even in the face of relapsed disease, has led to the consideration of a revised approach to frontline therapy. The advent of immune therapies such as checkpoint inhibition has provided another option for the treatment of ALCL. In fact, the number of potential new agents now presents a real challenge to the clinical community that must prioritise those thought to offer the most promise for the future. In this review, we will focus on the current status of paediatric ALCL therapy, explore how new and ‘renewed’ agents are re-shaping the therapeutic landscape for ALCL, and identify the strategies being employed in the next generation of clinical trials.