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      18F-FDG-PET/CT imaging in an IL-6- and MYC-driven mouse model of human multiple myeloma affords objective evaluation of plasma cell tumor progression and therapeutic response to the proteasome inhibitor ixazomib

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          Abstract

          18F-fluorodeoxyglucose positron emission tomography (FDG-PET) and computed tomography (CT) are useful imaging modalities for evaluating tumor progression and treatment responses in genetically engineered mouse models of solid human cancers, but the potential of integrated FDG-PET/CT for assessing tumor development and new interventions in transgenic mouse models of human blood cancers such as multiple myeloma (MM) has not been demonstrated. Here we use BALB/c mice that contain the newly developed iMyc ΔEμ gene insertion and the widely expressed H2-L d-IL6 transgene to demonstrate that FDG-PET/CT affords an excellent research tool for assessing interleukin-6- and MYC-driven plasma cell tumor (PCT) development in a serial, reproducible and stage- and lesion-specific manner. We also show that FDG-PET/CT permits determination of objective drug responses in PCT-bearing mice treated with the investigational proteasome inhibitor ixazomib (MLN2238), the biologically active form of ixazomib citrate (MLN9708), that is currently in phase 3 clinical trials in MM. Overall survival of 5 of 6 ixazomib-treated mice doubled compared with mice left untreated. One outlier mouse presented with primary refractory disease. Our findings demonstrate the utility of FDG-PET/CT for preclinical MM research and suggest that this method will play an important role in the design and testing of new approaches to treat myeloma.

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          Most cited references36

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          Cancer's molecular sweet tooth and the Warburg effect.

          More than 80 years ago, the renowned biochemist Otto Warburg described how cancer cells avidly consume glucose and produce lactic acid under aerobic conditions. Recent studies arguing that cancer cells benefit from this phenomenon, termed the Warburg effect, have renewed discussions about its exact role as cause, correlate, or facilitator of cancer. Molecular advances in this area may reveal tactics to exploit the cancer cell's "sweet tooth" for cancer therapy.
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            NPM-ALK transgenic mice spontaneously develop T-cell lymphomas and plasma cell tumors.

            Anaplastic Large Cell Lymphomas (ALCLs) carry translocations in which the anaplastic lymphoma kinase (ALK) gene is juxtaposed to various genes, the most common of which is the NPM/B23 gene. ALK fusion proteins result in the constitutive activation of ALK tyrosine kinase, thereby enhancing proliferation and increasing cell survival. A direct role for NPM-ALK in cellular transformation has been shown in vitro with immortalized cell lines and in vivo using retroviral transfer experiments. Nonetheless, there is no direct evidence of its oncogenic potential in T lymphocytes, which represent the most common target of ALK chimeras. Here, we describe a new mouse model of lymphomagenesis in which human NPM-ALK transcription was targeted to T cells. NPM-ALK transgenic (Tg) mice were born with the expected mendelian distribution, normal lymphoid organs, and a normal number and proportion of helper and suppressor T cells. However, after a short period of latency, all NPM-ALK Tg mice developed malignant lymphoproliferative disorders (mean survival, 18 weeks). NPM-ALK Tg thymic lymphomas displayed a T-cell phenotype characteristic of immature thymocytes and frequently coexpressed surface CD30. A subset of the NPM-ALK Tg mice also developed clonal B-cell plasma cell neoplasms. These tumors arose in peripheral lymphoid organs (plasmacytomas) or within the bone marrow and often led to peripheral neuropathies and limb paralysis. Our NPM-ALK Tg mice are a suitable model to dissect the molecular mechanisms of ALK-mediated transformation and to investigate the efficacy of new therapeutic approaches for the treatment of human ALCL in vivo.
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              IgG1 plasmacytosis in interleukin 6 transgenic mice.

              Interleukin 6 (IL-6) has been suggested to be involved in the pathogenesis of polyclonal and monoclonal plasma cell abnormalities. To address this possibility, transgenic mice carrying the human IL-6 genomic gene fused with a human immunoglobulin heavy chain enhancer were generated. High concentrations of human IL-6 and polyclonal increase in IgG1 (120- to 400-fold) in sera of all transgenic mice were observed. A massive plasmacytosis in thymus, lymph node, and spleen and an infiltration of plasma cells in lung, liver, and kidney were observed. However, the plasma cells were not transplantable to syngeneic mice and were found not to contain chromosomal aberrations including c-myc gene rearrangements. The evidence indicates that deregulated gene expression of IL-6 can trigger polyclonal plasmacytosis but cannot induce plasmacytoma. It is suggested that additional genetic changes may be required for the generation of plasma cell neoplasia. Other interesting findings in these transgenic mice were the development of mesangio-proliferative glomerulonephritis and an increase in megakaryocytes in bone marrow.
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                Author and article information

                Journal
                Blood Cancer J
                Blood Cancer J
                Blood Cancer Journal
                Nature Publishing Group
                2044-5385
                November 2013
                29 November 2013
                1 November 2013
                : 3
                : 11
                : e165
                Affiliations
                [1 ]Department of Pathology, University of Iowa Roy J and Lucille A Carver College of Medicine , Iowa City, IA, USA
                [2 ]The Interdisciplinary Immunology Graduate Program, University of Iowa Roy J and Lucille A Carver College of Medicine , Iowa City, IA, USA
                [3 ]The Bioinformatics Core Facility, University of Iowa Roy J and Lucille A Carver College of Medicine , Iowa City, IA, USA
                [4 ]Department of Internal Medicine, University of Iowa Roy J and Lucille A Carver College of Medicine , Iowa City, IA, USA
                [5 ]Department of Radiology, University of Iowa Roy J and Lucille A Carver College of Medicine , Iowa City, IA, USA
                [6 ]Takeda Pharmaceutica Company Ltd , Cambridge, MA, USA
                [7 ]Virology and Cellular Immunology Section, Laboratory of Immunogenetics, National Institutes of Allergy and Infectious Diseases, National Institutes of Health , Rockville, MD, USA
                Author notes
                [* ]Department of Radiology, University of Iowa Roy J and Lucille A Carver College of Medicine, 3881 JPP , Iowa City, 52242 IA, USA E-mail: john-sunderland@ 123456uiowa.edu
                [* ]Department of Pathology, Carver College of Medicine, University of Iowa , 500 Newton Road, 1046C ML, Iowa City, 52242 IA, USA. E-mail: siegfried-janz@ 123456uiowa.edu
                [8]

                These authors shared senior co-authorship.

                Article
                bcj201361
                10.1038/bcj.2013.61
                3880444
                24292417
                7da86e50-63eb-446c-a31f-9f23e02dc5cd
                Copyright © 2013 Macmillan Publishers Limited

                This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/

                History
                : 14 August 2013
                : 22 September 2013
                : 02 October 2013
                Categories
                Original Article

                Oncology & Radiotherapy
                gemm (genetically engineered mouse model) of human cancer,preclinical cancer drug testing,plasma cell neoplasia

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