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Voena C.,University of Turin | Voena C.,Center for Experimental Research and Medical Studies | Voena C.,Harvard University | Peola S.,University of Turin | And 5 more authors.
Frontiers in Bioscience - Scholar | Year: 2015

Twenty years ago anaplastic lymphoma kinase (ALK) was discovered in anaplastic large cell lymphoma (ALCL), but the interest in ALK as an oncogene grew only in recent years when ALK rearrangements were reported as recurrent genetic lesions in lung carcinoma and activating single point mutations were described in neuroblastoma. In this review we will describe the main features of ALK-rearranged solid tumors, with particular emphasis to NSCLC and neuroblastoma. We will discuss the numerous in vitro and in vivo studies that confirmed ALK as the "driver" oncogene in these tumors and the achievements in clinical settings with ALK inhibitors that validated ALK as a therapeutic target. We will finally end with the description of putative innovative therapeutic approaches that are on going to overcome acquired resistance that invariably occurs in crizotinib treated NSCLC patients or intrinsic resistance to crizotinb therapy reported in neuroblastoma. © 1996-2015.

Pizzi M.,University of Padua | Pizzi M.,New York Medical College | Gaudiano M.,New York Medical College | Todaro M.,New York Medical College | And 5 more authors.
Frontiers in Bioscience - Scholar | Year: 2015

The discovery of Anaplastic Lymphoma Kinase (ALK) by Stephan Morris and colleagues twenty years ago has led to an unprecedented opportunity and provided the basis for a novel and clinically powerful stratification of human cancers. The molecular and biological characterization of ALK and the recognition of alternative mechanisms of activation of the tyrosine kinase receptors have then set the basis for the development and the subsequent application of selective small molecules. These achievements have fostered a new era in oncology, and the result of this new avenue has drastically changed the expectation of many cancer patients. Here we review the mechanisms of ALK activation and the modalities that drive ALK pathogenesis. © 2015, Frontiers in Bioscience. All rights reserved.

Roukos V.,U.S. National Cancer Institute | Mathas S.,Max Delbrück Center for Molecular Medicine | Mathas S.,Charité - Medical University of Berlin | Mathas S.,German Cancer Research Center | Mathas S.,European Research Initiative on ALK related Malignancies ERIA
Frontiers in Bioscience - Scholar | Year: 2015

Translocations involving the anaplastic lymphoma kinase (ALK) gene locus on chromosome 2p23 were first described in anaplastic large cell lymphoma (ALCL). Although most commonly fused to the nucleophosmin (NPM1) gene on chromosome 5q35, which results in the t(2;5)(p23;q35)/NPM1-ALK translocation, several other ALK translocation partners have meanwhile been identified. Furthermore, apart from ALCL, ALK-involving translocations have been described in other hematopoietic and non-hematopoietic cancers. However, despite a rapid increase in literature on the nature and tissue distribution of ALK-translocations, much less is known about the mechanisms of formation of these translocations. The emergence of translocations has been linked to the transcriptional activity of the respective genome regions, reorganization of the chromatin and activation of the DNA repair machinery. In this review we discuss mechanisms and implications of formation of ALK-translocations. © 1996-2015.

Moti N.,University of Cambridge | Malcolm T.,University of Cambridge | Hamoudi R.,University of Cambridge | Mian S.,Hail University | And 13 more authors.
Oncogene | Year: 2014

Cancer stem cells or tumour-propagating cells (TPCs) have been identified for a number of cancers, but data pertaining to their existence in lymphoma so far remain elusive. We show for the first time that a small subset of cells purified from human anaplastic lymphoma kinase (ALK)-positive and -negative, anaplastic large cell lymphoma cell lines and primary patient tumours using the side population (SP) technique have serial tumour-propagating capacity both in vitro and in vivo; they give rise to both themselves and the bulk tumour population as well as supporting growth of the latter through the production of soluble factors. In vivo serial dilution assays utilising a variety of model systems inclusive of human cell lines, primary human tumours and nucleophosmin (NPM)-ALK-induced murine tumours demonstrate the TPC frequency to vary from as many as 1/54 to 1/1336 tumour cells. In addition, the SP cells express higher levels of pluripotency-associated transcription factors and are enriched for a gene expression profile consistent with early thymic progenitors. Finally, our data show that the SP cells express higher levels of the NPM-ALK oncogene and are sensitive to an ALK inhibitor.Oncogene advance online publication 12 May 2014; doi:10.1038/onc.2014.112.

Bergalet J.,Institute Of Recherches Cliniques Of Montreal Ircm | Fawal M.,Spanish National Cancer Research Center | Morello D.,University Paul Sabatier | Espinos E.,French Institute of Health and Medical Research | And 3 more authors.
Frontiers in Bioscience - Landmark | Year: 2015

Extensive research has been carried out in the past two decades to provide insights into the molecular mechanisms by which the Nucleophosmin-Anaplastic Lymphoma Kinase (NPM-ALK) exerts its oncogenic effects. These studies led to the concept that NPM-ALK acts at the transcriptional level through the activation of several transcription factors downstream of many different signaling pathways including JAK3/STAT3, PI3K/AKT and RAS/ERK. Nevertheless, the discovery of several RNA-binding proteins (RBPs) within ALK interactome suggested an additional and complementary role of this oncogenic kinase at the post-transcriptional level. This review gives emerging views in ALK-mediated post-transcriptional regulation with a focus on RBPs that are associated with ALK. We will summarize the capacity of NPM-ALK in modulating the biological properties of RBPs and then discuss the role of cytoplasmic aggregates, called AGs for "ALK granules", which are observed in anaplastic large cell lymphoma (ALCL) expressing the ALK kinase. AGs contain polyadenylated mRNAs and numerous RBPs but are distinct from processing bodies (PBs) and stress granules (SGs), two well-known discrete cytoplasmic sites involved in mRNA fate.

Mitou G.,French Institute of Health and Medical Research | Mitou G.,University Paul Sabatier | Mitou G.,French National Center for Scientific Research | Frentzel J.,French Institute of Health and Medical Research | And 28 more authors.
Oncotarget | Year: 2015

Anaplastic Lymphoma Kinase-positive Anaplastic Large Cell Lymphomas (ALK+ALCL) occur predominantly in children and young adults. Their treatment, based on aggressive chemotherapy, is not optimal since ALCL patients can still expect a 30% 2-year relapse rate. Tumor relapses are very aggressive and their underlying mechanisms are unknown. Crizotinib is the most advanced ALK tyrosine kinase inhibitor and is already used in clinics to treat ALK-associated cancers. However, crizotinib escape mechanisms have emerged, thus preventing its use in frontline ALCL therapy. The process of autophagy has been proposed as the next target for elimination of the resistance to tyrosine kinase inhibitors. In this study, we investigated whether autophagy is activated in ALCL cells submitted to ALK inactivation (using crizotinib or ALK-targeting siRNA). Classical autophagy read-outs such as autophagosome visualization/quantification by electron microscopy and LC3-B marker turn-over assays were used to demonstrate autophagy induction and flux activation upon ALK inactivation. This was demonstrated to have a cytoprotective role on cell viability and clonogenic assays following combined ALK and autophagy inhibition. Altogether, our results suggest that co-treatment with crizotinib and chloroquine (two drugs already used in clinics) could be beneficial for ALK-positive ALCL patients.

Giuriato S.,French Institute of Health and Medical Research | Giuriato S.,University Paul Sabatier | Giuriato S.,French National Center for Scientific Research | Giuriato S.,European Research Initiative on ALK related Malignancies ERIA | And 2 more authors.
Frontiers in Bioscience - Scholar | Year: 2015

Our current understanding of oncogenic Anaplastic Lymphoma Kinase (ALK)-induced lymphomagenesis has relied for over 20 years on multiple and complementary studies performed on various experimental models, encompassing ALK oncogene expressing cells, their grafts into immune-compromised mice, the generation of genetically engineered mouse models (GEMMs) and, when available, the use of patient samples from Anaplastic Large Cell Lymphoma (ALCL) tumour banks. Of note, and to our knowledge, no ALK-positive ALCL 3D culture system has been described so far. In this review, we will first outline how these different cell and mouse models were designed, and what key findings they revealed (or confirmed) towards oncogenic ALK-induced lymphomagenesis. Secondly, we will discuss how recent and revolutionary advances in genetic engineering technology are likely to complete our understanding of ALK-related diseases in an effort to improve current therapeutic approaches. © 2015, Frontiers in Bioscience. All rights reserved.

Schiefer A.-I.,Medical University of Vienna | Vesely P.,Medical University of Graz | Vesely P.,University of Graz | Hassler M.R.,Medical University of Vienna | And 6 more authors.
Frontiers in Bioscience - Scholar | Year: 2015

Anaplastic large cell lymphoma (ALCL) is an aggressive, highly proliferative, T-cell lymphoma with increasing incidence worldwide. Anaplastic Lymphoma Kinase (ALK) fusions occur in about 50% of all cases. Most ALK positive cases of ALCL harbor the t(2;5) translocation that leads to expression of Nucleophosmin-Anaplastic Lymphoma Kinase (NPM-ALK). NPM-ALK induces a variety of oncogenic signaling pathways that lead to malignant transformation of T-cells via Activator Protein-1 (AP-1), STAT3 and other (transcription) factors. In addition to the commonly known AP-1 activators Mitogen-Activated Protein Kinases (MAPKs), there are other signaling pathways, such as PI3K/mTOR/AKT, which are implicated in AP-1 activation/expression in ALCL. The AP-1 factor JUNB was shown to drive ALCL proliferation and the expression of the characteristic ALCL Ki-1 antigen, CD30. cJUN and JUNB target PDGFRB, thereby leading to tumor progression and dissemination. Furthermore, aberrant gene expression in ALCL is frequently accompanied by changes in epigenetic regulatory mechanisms, such as DNA methylation patterns. Here, we discuss the role of AP-1 in the pathogenesis of ALCL and provide an overview of pathological epigenetic changes in ALCL cells. © 2015, Frontiers in Bioscience. All rights reserved.

Damm-Welk C.,Justus Liebig University | Damm-Welk C.,European Research Initiative on ALK related Malignancies ERIA | Pillon M.,National Research Council Italy | Pillon M.,University of Padua | And 5 more authors.
Frontiers in Bioscience - Scholar | Year: 2015

Event-free survival of children and adolescents with ALK-positive anaplastic large cell lymphoma (ALCL) reaches 65-75% with current chemotherapy regimen. Risk stratification of children with ALCL was, until now, based on clinical parameters. More recently, pathological and biological risk factors have been described in trials applying BFM-type chemotherapy. Histological subtypes containing small-cell or lymphohistiocytic components indicate a high risk of failure. Minimal disseminated disease (MDD) detected by qualitative RT-PCR for NPM-ALK in bone marrow or blood is associated with a relapse risk of 50%. Quantification of MDD and persistent minimal residual disease (MRD) characterize very high risk patients. Serum ALK-autoantibody titres inversely correlate with relapse risk. The combination of MDD and ALK-antibody titre separates both low and very high risk patients from those with standard risk. In relapse, the time of relapse/progression, central nervous system and bone marrow involvement are major risk factors. In conclusion, MDD, MRD, ALK-antibody titres and histological subtype are strong biological risk factors in childhood ALCL. The combination of MDD and ALK-antibody titre may serve for patient stratification in upcoming clinical trials. © 1996-2015.

Bonzheim I.,University of Tübingen | Steinhilber J.,University of Tübingen | Fend F.,University of Tübingen | Lamant L.,Hopital Purpan | And 2 more authors.
Frontiers in Bioscience - Scholar | Year: 2015

The current classification of lymphoid neoplasms is based on the integrated utilisation of morphological, immunohistochemical, genetic and clinical criteria to define disease entities. Anaplastic large cell lymphoma is a paradigm for the identification of a disease entity based on morphological observations and immunophenotype, which paved the way for the subsequent discovery of the characteristic cytogenetic abnormality the translocation t(2;5) (p23;q35). In 1994, the t(2;5) was cloned and the NPM-ALK fusion gene generated by this rearrangement was identified. The year 2014 marked the 20thanniversary of this seminal publication by Steve Morris et al. The discovery of anaplastic lymphoma kinase (ALK) has allowed the definition of a distinct entity within the clinically and pathologically heterogeneous group of CD30+ lymphomas. The diagnosis of ALK-positive ALCL has become straightforward due to the generation of the reliable monoclonal antibody ALK-1 that also has led to the recognition of the histologic spectrum of the disease. ALK-positive ALCL has evolved in the last 20 years to an exciting model for signal transduction studies and targeted therapy. © 1996-2015.

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