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      Sensitivity Analysis of the NPM-ALK Signalling Network Reveals Important Pathways for Anaplastic Large Cell Lymphoma Combination Therapy

      1 , 2 , 3 , 4 , * , 5 , 6 , 1 , 2 , *

      PLoS ONE

      Public Library of Science

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          Abstract

          A large subset of anaplastic large cell lymphoma (ALCL) patients harbour a somatic aberration in which anaplastic lymphoma kinase (ALK) is fused to nucleophosmin (NPM) resulting in a constitutively active signalling fusion protein, NPM-ALK. We computationally simulated the signalling network which mediates pathological cell survival and proliferation through NPM-ALK to identify therapeutically targetable nodes through which it may be possible to regain control of the tumourigenic process. The simulations reveal the predominant role of the VAV1-CDC42 (cell division control protein 42) pathway in NPM-ALK-driven cellular proliferation and of the Ras / mitogen-activated ERK kinase (MEK) / extracellular signal-regulated kinase (ERK) cascade in controlling cell survival. Our results also highlight the importance of a group of interleukins together with the Janus kinase 3 (JAK3) / signal transducer and activator of transcription 3 (STAT3) signalling in the development of NPM-ALK derived ALCL. Depending on the activity of JAK3 and STAT3, the system may also be sensitive to activation of protein tyrosine phosphatase-1 (SHP1), which has an inhibitory effect on cell survival and proliferation. The identification of signalling pathways active in tumourigenic processes is of fundamental importance for effective therapies. The prediction of alternative pathways that circumvent classical therapeutic targets opens the way to preventive approaches for countering the emergence of cancer resistance.

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          Most cited references 68

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          Is Open Access

          Error and attack tolerance of complex networks

          Many complex systems, such as communication networks, display a surprising degree of robustness: while key components regularly malfunction, local failures rarely lead to the loss of the global information-carrying ability of the network. The stability of these complex systems is often attributed to the redundant wiring of the functional web defined by the systems' components. In this paper we demonstrate that error tolerance is not shared by all redundant systems, but it is displayed only by a class of inhomogeneously wired networks, called scale-free networks. We find that scale-free networks, describing a number of systems, such as the World Wide Web, Internet, social networks or a cell, display an unexpected degree of robustness, the ability of their nodes to communicate being unaffected by even unrealistically high failure rates. However, error tolerance comes at a high price: these networks are extremely vulnerable to attacks, i.e. to the selection and removal of a few nodes that play the most important role in assuring the network's connectivity.
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            Is Open Access

            The large-scale organization of metabolic networks

            In a cell or microorganism the processes that generate mass, energy, information transfer, and cell fate specification are seamlessly integrated through a complex network of various cellular constituents and reactions. However, despite the key role these networks play in sustaining various cellular functions, their large-scale structure is essentially unknown. Here we present the first systematic comparative mathematical analysis of the metabolic networks of 43 organisms representing all three domains of life. We show that, despite significant variances in their individual constituents and pathways, these metabolic networks display the same topologic scaling properties demonstrating striking similarities to the inherent organization of complex non-biological systems. This suggests that the metabolic organization is not only identical for all living organisms, but complies with the design principles of robust and error-tolerant scale-free networks, and may represent a common blueprint for the large-scale organization of interactions among all cellular constituents.
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              Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma.

              The 2;5 chromosomal translocation occurs in most anaplastic large-cell non-Hodgkin's lymphomas arising from activated T lymphocytes. This rearrangement was shown to fuse the NPM nucleolar phosphoprotein gene on chromosome 5q35 to a previously unidentified protein tyrosine kinase gene, ALK, on chromosome 2p23. In the predicted hybrid protein, the amino terminus of nucleophosmin (NPM) is linked to the catalytic domain of anaplastic lymphoma kinase (ALK). Expressed in the small intestine, testis, and brain but not in normal lymphoid cells, ALK shows greatest sequence similarity to the insulin receptor subfamily of kinases. Unscheduled expression of the truncated ALK may contribute to malignant transformation in these lymphomas.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                2016
                26 September 2016
                : 11
                : 9
                Affiliations
                [1 ]Department of Chemistry and Biomedical Sciences, Linnæus University, Kalmar, Sweden
                [2 ]Linnæus University Centre for Biomaterials Chemistry, Linnæus University, Kalmar, Sweden
                [3 ]Institute of Computational Science, Faculty of Informatics, Università della Svizzera Italiana, Lugano, Switzerland
                [4 ]Swiss Institute of Bioinformatics, Lausanne, Switzerland
                [5 ]Huntsman Cancer Institute, The University of Utah, Salt Lake City, United States of America
                [6 ]Division of Hematology and Hematologic Malignancies, The University of Utah, Salt Lake City, United States of America
                Queen’s University Belfast, UNITED KINGDOM
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                • Conceived and designed the experiments: AB TO RF.

                • Performed the experiments: AB.

                • Analyzed the data: AB TO RF.

                • Contributed reagents/materials/analysis tools: AB RF.

                • Wrote the paper: AB TO RF.

                [¤a]

                Current address: Department of Chemistry and Biomedical Sciences, Norra vägen 49, SE-391 82 Kalmar, Sweden

                [¤b]

                Current address: Huntsman Cancer Institute, HCI4264, 2000 Circle of Hope, Salt Lake City, UT 84112, United States of America

                Article
                PONE-D-16-08983
                10.1371/journal.pone.0163011
                5036789
                27669408

                This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

                Page count
                Figures: 4, Tables: 0, Pages: 17
                Product
                Funding
                Funded by: Holcim Stiftung
                Award Recipient :
                This work was supported by Holcim Foundation (Switzerland, to Antoine Buetti-Dinh). No grant number. URL: http://www.holcim-stiftung.ch/. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Computer and Information Sciences
                Network Analysis
                Signaling Networks
                Biology and life sciences
                Cell biology
                Signal transduction
                Cell signaling
                STAT signaling
                Biology and Life Sciences
                Cell Biology
                Signal Transduction
                Cell Signaling
                Signaling Cascades
                Protein Kinase Signaling Cascade
                Biology and Life Sciences
                Physiology
                Immune Physiology
                Cytokines
                Interleukins
                Medicine and Health Sciences
                Physiology
                Immune Physiology
                Cytokines
                Interleukins
                Biology and Life Sciences
                Immunology
                Immune System
                Innate Immune System
                Cytokines
                Interleukins
                Medicine and Health Sciences
                Immunology
                Immune System
                Innate Immune System
                Cytokines
                Interleukins
                Biology and Life Sciences
                Developmental Biology
                Molecular Development
                Cytokines
                Interleukins
                Biology and life sciences
                Cell biology
                Signal transduction
                Cell signaling
                Signaling cascades
                ERK signaling cascade
                Computer and Information Sciences
                Network Analysis
                Biology and Life Sciences
                Cell Biology
                Signal Transduction
                Cell Signaling
                Signal Inhibition
                Medicine and Health Sciences
                Oncology
                Cancers and Neoplasms
                Hematologic Cancers and Related Disorders
                Lymphomas
                Medicine and Health Sciences
                Hematology
                Hematologic Cancers and Related Disorders
                Lymphomas
                Custom metadata
                Program source code, input files and simulations raw data files are available from the Figshare repository ( https://figshare.com/s/c020b5b8f10d445e8881; DOI: 10.6084/m9.figshare.3814554).

                Uncategorized

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