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animals, pubmed, tca, cll, fig, article, tcp, atm, cells, google, scholar, mice, cas, supplementary, treatment, cell, leukemia, disease, cyclophosphamide, blood, leukemic, weeks, chronic, lymphocytic, trp, data, dna, response, expression, nature, compared, genes, central, parp, survival, spleen, repair, analysis, patients, shown, mouse, models, observed, cologne, significantly, human, ttest, performed, age, highrisk,

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nature portfolio mixed c57bl/6j-c57bl/6n background atm/chk2/brca1/brca2/palb2-dependent fashion32 privacy policy guanidinium thiocyanate-phenol-chloroform extraction ideal preclinical tools imalytics research workstation advertising philips research europe proliferation index phospho-ser/thr-binding domains pe-vio770 anti-mouse cd5 social media cll research received fludarabine/cyclophosphamide-based chemotherapy metabolism research 12 libraries reprints dna double-strand break dna double-strand breaks nature 526 nature nature 434 pe anti-mouse/human cd44 open-label high-risk genetic aberrations age-matched wild-type controls conditional b-cell-specific deletion atm-defective high-risk cll flow cytometry-based assessment pe anti-mouse cd184 chronic lymphocytic leukaemia kegg pathway-based analysis25 fine-grained genomic understanding trp53-mediated apoptotic signaling obvious genotype-directed clustering rpa-coated ssdna filament flow cytometry-based quantification chronic lymphocytic leukemia chronic lymphocytic leukemia manuel montesinos-rongen p53-null mutant mice vioblue anti-mouse cd19 viogreen anti-mouse cd45 labeled with32p-α-ctp fitc anti-mouse cd182 hr-mediated dsb repair dsb repair—homologous recombination original author atm-dependent repair defect

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• Prognostic factors in chronic lymphocytic leukemia-what do we need to know?

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         headline:Two mouse models reveal an actionable PARP1 dependence in aggressive chronic lymphocytic leukemia
         description:Chronic lymphocytic leukemia (CLL) remains an incurable disease. Two recurrent cytogenetic aberrations, namely del(17p), affecting TP53, and del(11q), affecting ATM, are associated with resistance against genotoxic chemotherapy (del17p) and poor outcome (del11q and del17p). Both del(17p) and del(11q) are also associated with inferior outcome to the novel targeted agents, such as the BTK inhibitor ibrutinib. Thus, even in the era of targeted therapies, CLL with alterations in the ATM/p53 pathway remains a clinical challenge. Here we generated two mouse models of Atm- and Trp53-deficient CLL. These animals display a significantly earlier disease onset and reduced overall survival, compared to controls. We employed these models in conjunction with transcriptome analyses following cyclophosphamide treatment to reveal that Atm deficiency is associated with an exquisite and genotype-specific sensitivity against PARP inhibition. Thus, we generate two aggressive CLL models and provide a preclinical rational for the use of PARP inhibitors in ATM-affected human CLL. ATM and TP53 mutations are associated with poor prognosis in chronic lymphocytic leukaemia (CLL). Here the authors generate mouse models of Tp53- and Atm-defective CLL mimicking the high-risk form of human disease and show that Atm-deficient CLL is sensitive to PARP1 inhibition.
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      headline:Two mouse models reveal an actionable PARP1 dependence in aggressive chronic lymphocytic leukemia
      description:Chronic lymphocytic leukemia (CLL) remains an incurable disease. Two recurrent cytogenetic aberrations, namely del(17p), affecting TP53, and del(11q), affecting ATM, are associated with resistance against genotoxic chemotherapy (del17p) and poor outcome (del11q and del17p). Both del(17p) and del(11q) are also associated with inferior outcome to the novel targeted agents, such as the BTK inhibitor ibrutinib. Thus, even in the era of targeted therapies, CLL with alterations in the ATM/p53 pathway remains a clinical challenge. Here we generated two mouse models of Atm- and Trp53-deficient CLL. These animals display a significantly earlier disease onset and reduced overall survival, compared to controls. We employed these models in conjunction with transcriptome analyses following cyclophosphamide treatment to reveal that Atm deficiency is associated with an exquisite and genotype-specific sensitivity against PARP inhibition. Thus, we generate two aggressive CLL models and provide a preclinical rational for the use of PARP inhibitors in ATM-affected human CLL. ATM and TP53 mutations are associated with poor prognosis in chronic lymphocytic leukaemia (CLL). Here the authors generate mouse models of Tp53- and Atm-defective CLL mimicking the high-risk form of human disease and show that Atm-deficient CLL is sensitive to PARP1 inhibition.
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            name:University of Cologne
            address:
               name:Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
               type:PostalAddress
            type:Organization
            name:University Hospital of Cologne
            address:
               name:Center of Integrated Oncology (CIO), University Hospital of Cologne, Cologne, Germany
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            type:Organization
      name:Darya Korovkina
      affiliation:
            name:University Hospital of Cologne
            address:
               name:Clinic I of Internal Medicine, University Hospital of Cologne, Cologne, Germany
               type:PostalAddress
            type:Organization
            name:University of Cologne
            address:
               name:Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
               type:PostalAddress
            type:Organization
            name:University Hospital of Cologne
            address:
               name:Center of Integrated Oncology (CIO), University Hospital of Cologne, Cologne, Germany
               type:PostalAddress
            type:Organization
      name:Paul Liedgens
      affiliation:
            name:University Hospital of Cologne
            address:
               name:Clinic I of Internal Medicine, University Hospital of Cologne, Cologne, Germany
               type:PostalAddress
            type:Organization
            name:University of Cologne
            address:
               name:Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
               type:PostalAddress
            type:Organization
            name:University Hospital of Cologne
            address:
               name:Center of Integrated Oncology (CIO), University Hospital of Cologne, Cologne, Germany
               type:PostalAddress
            type:Organization
      name:Christian Fritz
      affiliation:
            name:University Hospital of Cologne
            address:
               name:Clinic I of Internal Medicine, University Hospital of Cologne, Cologne, Germany
               type:PostalAddress
            type:Organization
            name:University of Cologne
            address:
               name:Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
               type:PostalAddress
            type:Organization
            name:University Hospital of Cologne
            address:
               name:Center of Integrated Oncology (CIO), University Hospital of Cologne, Cologne, Germany
               type:PostalAddress
            type:Organization
      name:Alessandro Torgovnick
      affiliation:
            name:University Hospital of Cologne
            address:
               name:Clinic I of Internal Medicine, University Hospital of Cologne, Cologne, Germany
               type:PostalAddress
            type:Organization
            name:University of Cologne
            address:
               name:Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
               type:PostalAddress
            type:Organization
            name:University Hospital of Cologne
            address:
               name:Center of Integrated Oncology (CIO), University Hospital of Cologne, Cologne, Germany
               type:PostalAddress
            type:Organization
      name:Yussor Al-Baldawi
      affiliation:
            name:University Hospital of Cologne
            address:
               name:Department of Radiology, Medical Faculty, University Hospital of Cologne, Cologne, Germany
               type:PostalAddress
            type:Organization
      name:Mona Al-Maarri
      affiliation:
            name:Max-Planck-Institute for Metabolism Research
            address:
               name:Max-Planck-Institute for Metabolism Research, Cologne, Germany
               type:PostalAddress
            type:Organization
      name:Yupeng Cun
      affiliation:
            name:University of Cologne
            address:
               name:Department of Translational Genomics, University of Cologne, Cologne, Germany
               type:PostalAddress
            type:Organization
      name:Oleg Fedorchenko
      affiliation:
            name:University Hospital of Cologne
            address:
               name:Clinic I of Internal Medicine, University Hospital of Cologne, Cologne, Germany
               type:PostalAddress
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            name:University of Cologne
            address:
               name:Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
               type:PostalAddress
            type:Organization
            name:University Hospital of Cologne
            address:
               name:Center of Integrated Oncology (CIO), University Hospital of Cologne, Cologne, Germany
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      name:Arina Riabinska
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            name:University Hospital of Cologne
            address:
               name:Clinic I of Internal Medicine, University Hospital of Cologne, Cologne, Germany
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            type:Organization
            name:University of Cologne
            address:
               name:Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
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            type:Organization
            name:University Hospital of Cologne
            address:
               name:Center of Integrated Oncology (CIO), University Hospital of Cologne, Cologne, Germany
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      name:Filippo Beleggia
      affiliation:
            name:University Hospital of Cologne
            address:
               name:Clinic I of Internal Medicine, University Hospital of Cologne, Cologne, Germany
               type:PostalAddress
            type:Organization
            name:University of Cologne
            address:
               name:Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
               type:PostalAddress
            type:Organization
            name:University Hospital of Cologne
            address:
               name:Center of Integrated Oncology (CIO), University Hospital of Cologne, Cologne, Germany
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            type:Organization
      name:Phuong-Hien Nguyen
      affiliation:
            name:University Hospital of Cologne
            address:
               name:Clinic I of Internal Medicine, University Hospital of Cologne, Cologne, Germany
               type:PostalAddress
            type:Organization
            name:University of Cologne
            address:
               name:Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
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            name:University Hospital of Cologne
            address:
               name:Center of Integrated Oncology (CIO), University Hospital of Cologne, Cologne, Germany
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      name:F. Thomas Wunderlich
      affiliation:
            name:Max-Planck-Institute for Metabolism Research
            address:
               name:Max-Planck-Institute for Metabolism Research, Cologne, Germany
               type:PostalAddress
            type:Organization
      name:Monika Ortmann
      affiliation:
            name:University Hospital of Cologne
            address:
               name:Institute of Pathology, University Hospital of Cologne, Cologne, Germany
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            type:Organization
      name:Manuel Montesinos-Rongen
      affiliation:
            name:University Hospital of Cologne
            address:
               name:Institute of Neuropathology, University Hospital of Cologne, Cologne, Germany
               type:PostalAddress
            type:Organization
      name:Eugen Tausch
      affiliation:
            name:Ulm University
            address:
               name:Department of Internal Medicine III, Ulm University, Ulm, Germany
               type:PostalAddress
            type:Organization
      name:Stephan Stilgenbauer
      affiliation:
            name:Ulm University
            address:
               name:Department of Internal Medicine III, Ulm University, Ulm, Germany
               type:PostalAddress
            type:Organization
      name:Lukas P. Frenzel
      affiliation:
            name:University Hospital of Cologne
            address:
               name:Clinic I of Internal Medicine, University Hospital of Cologne, Cologne, Germany
               type:PostalAddress
            type:Organization
            name:University of Cologne
            address:
               name:Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
               type:PostalAddress
            type:Organization
            name:University Hospital of Cologne
            address:
               name:Center of Integrated Oncology (CIO), University Hospital of Cologne, Cologne, Germany
               type:PostalAddress
            type:Organization
      name:Marco Herling
      affiliation:
            name:University Hospital of Cologne
            address:
               name:Clinic I of Internal Medicine, University Hospital of Cologne, Cologne, Germany
               type:PostalAddress
            type:Organization
            name:University of Cologne
            address:
               name:Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
               type:PostalAddress
            type:Organization
            name:University Hospital of Cologne
            address:
               name:Center of Integrated Oncology (CIO), University Hospital of Cologne, Cologne, Germany
               type:PostalAddress
            type:Organization
            name:University of Cologne
            address:
               name:Center of Molecular Medicine, University of Cologne, Cologne, Germany
               type:PostalAddress
            type:Organization
      name:Carmen Herling
      affiliation:
            name:University Hospital of Cologne
            address:
               name:Clinic I of Internal Medicine, University Hospital of Cologne, Cologne, Germany
               type:PostalAddress
            type:Organization
            name:University Hospital of Cologne
            address:
               name:Center of Integrated Oncology (CIO), University Hospital of Cologne, Cologne, Germany
               type:PostalAddress
            type:Organization
      name:Jasmin Bahlo
      affiliation:
            name:University Hospital of Cologne
            address:
               name:Clinic I of Internal Medicine, University Hospital of Cologne, Cologne, Germany
               type:PostalAddress
            type:Organization
      name:Michael Hallek
      affiliation:
            name:University Hospital of Cologne
            address:
               name:Clinic I of Internal Medicine, University Hospital of Cologne, Cologne, Germany
               type:PostalAddress
            type:Organization
            name:University of Cologne
            address:
               name:Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
               type:PostalAddress
            type:Organization
            name:University Hospital of Cologne
            address:
               name:Center of Integrated Oncology (CIO), University Hospital of Cologne, Cologne, Germany
               type:PostalAddress
            type:Organization
      name:Martin Peifer
      affiliation:
            name:University of Cologne
            address:
               name:Department of Translational Genomics, University of Cologne, Cologne, Germany
               type:PostalAddress
            type:Organization
      name:Reinhard Buettner
      affiliation:
            name:University Hospital of Cologne
            address:
               name:Center of Integrated Oncology (CIO), University Hospital of Cologne, Cologne, Germany
               type:PostalAddress
            type:Organization
            name:University Hospital of Cologne
            address:
               name:Institute of Pathology, University Hospital of Cologne, Cologne, Germany
               type:PostalAddress
            type:Organization
      name:Thorsten Persigehl
      affiliation:
            name:University Hospital of Cologne
            address:
               name:Department of Radiology, Medical Faculty, University Hospital of Cologne, Cologne, Germany
               type:PostalAddress
            type:Organization
      name:H. Christian Reinhardt
      affiliation:
            name:University Hospital of Cologne
            address:
               name:Clinic I of Internal Medicine, University Hospital of Cologne, Cologne, Germany
               type:PostalAddress
            type:Organization
            name:University of Cologne
            address:
               name:Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
               type:PostalAddress
            type:Organization
            name:University Hospital of Cologne
            address:
               name:Center of Integrated Oncology (CIO), University Hospital of Cologne, Cologne, Germany
               type:PostalAddress
            type:Organization
            name:University of Cologne
            address:
               name:Center of Molecular Medicine, University of Cologne, Cologne, Germany
               type:PostalAddress
            type:Organization
      email:[email protected]
PostalAddress:
      name:Clinic I of Internal Medicine, University Hospital of Cologne, Cologne, Germany
      name:Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
      name:Center of Integrated Oncology (CIO), University Hospital of Cologne, Cologne, Germany
      name:Clinic I of Internal Medicine, University Hospital of Cologne, Cologne, Germany
      name:Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
      name:Center of Integrated Oncology (CIO), University Hospital of Cologne, Cologne, Germany
      name:Clinic I of Internal Medicine, University Hospital of Cologne, Cologne, Germany
      name:Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
      name:Center of Integrated Oncology (CIO), University Hospital of Cologne, Cologne, Germany
      name:Clinic I of Internal Medicine, University Hospital of Cologne, Cologne, Germany
      name:Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
      name:Center of Integrated Oncology (CIO), University Hospital of Cologne, Cologne, Germany
      name:Clinic I of Internal Medicine, University Hospital of Cologne, Cologne, Germany
      name:Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
      name:Center of Integrated Oncology (CIO), University Hospital of Cologne, Cologne, Germany
      name:Clinic I of Internal Medicine, University Hospital of Cologne, Cologne, Germany
      name:Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
      name:Center of Integrated Oncology (CIO), University Hospital of Cologne, Cologne, Germany
      name:Department of Radiology, Medical Faculty, University Hospital of Cologne, Cologne, Germany
      name:Max-Planck-Institute for Metabolism Research, Cologne, Germany
      name:Department of Translational Genomics, University of Cologne, Cologne, Germany
      name:Clinic I of Internal Medicine, University Hospital of Cologne, Cologne, Germany
      name:Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
      name:Center of Integrated Oncology (CIO), University Hospital of Cologne, Cologne, Germany
      name:Clinic I of Internal Medicine, University Hospital of Cologne, Cologne, Germany
      name:Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
      name:Center of Integrated Oncology (CIO), University Hospital of Cologne, Cologne, Germany
      name:Clinic I of Internal Medicine, University Hospital of Cologne, Cologne, Germany
      name:Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
      name:Center of Integrated Oncology (CIO), University Hospital of Cologne, Cologne, Germany
      name:Clinic I of Internal Medicine, University Hospital of Cologne, Cologne, Germany
      name:Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
      name:Center of Integrated Oncology (CIO), University Hospital of Cologne, Cologne, Germany
      name:Max-Planck-Institute for Metabolism Research, Cologne, Germany
      name:Institute of Pathology, University Hospital of Cologne, Cologne, Germany
      name:Institute of Neuropathology, University Hospital of Cologne, Cologne, Germany
      name:Department of Internal Medicine III, Ulm University, Ulm, Germany
      name:Department of Internal Medicine III, Ulm University, Ulm, Germany
      name:Clinic I of Internal Medicine, University Hospital of Cologne, Cologne, Germany
      name:Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
      name:Center of Integrated Oncology (CIO), University Hospital of Cologne, Cologne, Germany
      name:Clinic I of Internal Medicine, University Hospital of Cologne, Cologne, Germany
      name:Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
      name:Center of Integrated Oncology (CIO), University Hospital of Cologne, Cologne, Germany
      name:Center of Molecular Medicine, University of Cologne, Cologne, Germany
      name:Clinic I of Internal Medicine, University Hospital of Cologne, Cologne, Germany
      name:Center of Integrated Oncology (CIO), University Hospital of Cologne, Cologne, Germany
      name:Clinic I of Internal Medicine, University Hospital of Cologne, Cologne, Germany
      name:Clinic I of Internal Medicine, University Hospital of Cologne, Cologne, Germany
      name:Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
      name:Center of Integrated Oncology (CIO), University Hospital of Cologne, Cologne, Germany
      name:Department of Translational Genomics, University of Cologne, Cologne, Germany
      name:Center of Integrated Oncology (CIO), University Hospital of Cologne, Cologne, Germany
      name:Institute of Pathology, University Hospital of Cologne, Cologne, Germany
      name:Department of Radiology, Medical Faculty, University Hospital of Cologne, Cologne, Germany
      name:Clinic I of Internal Medicine, University Hospital of Cologne, Cologne, Germany
      name:Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
      name:Center of Integrated Oncology (CIO), University Hospital of Cologne, Cologne, Germany
      name:Center of Molecular Medicine, University of Cologne, Cologne, Germany

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