Kooperativer Bibliotheksverbund

Berlin Brandenburg


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  • 1
    In: European Journal of Immunology, September 2014, Vol.44(9), pp.2785-2801
    Description: Unless stimulated by a chronic inflammatory agent, such as mineral oil, plasma cell tumors are rare in young BALB/c mice. This raises the questions: What do inflammatory tissues provide to promote mutagenesis? And what is the nature of mutagenesis? We determined that mineral oil‐induced plasmacytomas produce large amounts of endogenous retroelements—ecotropic and polytropic murine leukemia virus and intracisternal A particles. Therefore, plasmacytoma formation might occur, in part, by de novo insertion of these retroelements, induced or helped by the inflammation. We recovered up to ten de novo insertions in a single plasmacytoma, mostly in genes with common retroviral integration sites. Additional integrations accompany tumor evolution from a solid tumor through several generations in cell culture. The high frequency of de novo integrations into cancer genes suggests that endogenous retroelements are coresponsible for plasmacytoma formation and progression in BALB/c mice.
    Keywords: Endogenous Retroelements ; Inflammation ; Mutagenesis ; Plasmacytomas ; Tumor Evolution
    ISSN: 0014-2980
    E-ISSN: 1521-4141
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  • 2
    Language: English
    In: Cancer research, 01 June 2017, Vol.77(11), pp.3040-3056
    Description: Defects in maintaining genome integrity are a hallmark of cancer. The DNA damage response kinase ATM is frequently mutated in human cancer, but the significance of these events to chemotherapeutic efficacy has not been examined deeply in whole organism models. Here we demonstrate that bi-allelic deletion in mouse models of -mutant lung adenocarcinoma does not affect cisplatin responses. In marked contrast, -deficient tumors displayed an enhanced response to the topoisomerase-II poison etoposide. Moreover, -deficient cells and tumors were sensitive to the PARP inhibitor olaparib. This actionable molecular addiction to functional PARP1 signaling was preserved in models that were proficient or deficient in p53, resembling standard or high-risk genetic constellations, respectively. deficiency also markedly enhanced sensitivity to the ATR inhibitor VE-822. Taken together, our results provide a functional rationale to profile human tumors for disabling mutations, particularly given their impact on PARP1 and ATR inhibitors. .
    Keywords: Adenocarcinoma -- Drug Therapy ; Ataxia Telangiectasia Mutated Proteins -- Metabolism ; Lung Neoplasms -- Drug Therapy ; Poly(Adp-Ribose) Polymerase Inhibitors -- Therapeutic Use
    ISSN: 00085472
    E-ISSN: 1538-7445
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  • 3
    Language: English
    In: Frontiers in genetics, 2015, Vol.6, pp.207
    Description: Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in the Western world and accounts for approximately 30% of adult leukemias and 25% of non-Hodgkin lymphomas. The median age at diagnosis is 72 years. During recent years numerous genetic aberrations have been identified that are associated with an aggressive course of the disease and resistance against genotoxic chemotherapies. The DNA damage-responsive proapoptotic ATM-CHK2-p53 signaling pathway is frequently mutationally inactivated in CLL either through large deletions on chromosome 11q (ATM) or 17p (TP53), or through protein-damaging mutations. Here, we focus on the role of ATM signaling for the immediate DNA damage response, DNA repair and leukemogenesis. We further discuss novel therapeutic concepts for the targeted treatment of ATM-defective CLLs. We specifically highlight the potential use of PARP1 and DNA-PKcs inhibitors for the treatment of ATM-mutant CLL clones. Lastly, we briefly discuss the current state of genetically engineered mouse models of the disease and emphasize the use of these preclinical tools as a common platform for the development and validation of novel therapeutic agents.
    Keywords: DNA Damage Response ; DNA-Pkcs Inhibitor ; Parp Inhibitor ; Chronic Lymphocytic Leukemia ; Precision Medicine
    ISSN: 1664-8021
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  • 4
    Language: English
    In: The Journal of general virology, November 2015, Vol.96(11), pp.3396-410
    Description: Murine leukaemia virus has been suggested to contribute to both autoimmune disease and leukaemia in the NZB mouse and in the (NZB × NZW) F1 (abbreviated B/W) mouse. However, with apparently only xenotropic but no ecotropic virus constitutively expressed in these mice, few mechanisms could explain the aetiology of either disease in either mouse strain. Because pseudotyped and/or inducible ecotropic virus may play a role, we surveyed the ability of murine leukaemia virus in NZB, NZW and B/W mice to infect and form a provirus. From the spleen of NZB mice, we isolated circular cDNA of xenotropic and polytropic virus, which indicates ongoing infection by these viruses. From a B/W lymphoma, we isolated and determined the complete sequence of a putative ecotropic NZW virus. From B/W mice, we recovered de novo endogenous retroviral integration sites (tags) from the hyperproliferating cells of the spleen and the peritoneum. The tagged genes seemed to be selected to aid cellular proliferation, as several of them are known cancer genes. The insertions are consistent with the idea that endogenous retrovirus contributes to B-cell hyperproliferation and progression to lymphoma in B/W mice.
    Keywords: Autoimmune Diseases -- Veterinary ; Endogenous Retroviruses -- Genetics ; Leukemia Virus, Murine -- Genetics ; Lymphoma -- Veterinary ; Mice, Inbred Nzb -- Virology ; Rodent Diseases -- Virology
    ISSN: 00221317
    E-ISSN: 1465-2099
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  • 5
    In: Current Opinion in Hematology, 2018, Vol.25(4), pp.315-322
    Description: PURPOSE OF REVIEW: Recent lymphoma genome sequencing projects have shed light on the genomic landscape of indolent and aggressive lymphomas, as well as some of the molecular mechanisms underlying recurrent mutations and translocations in these entities. Here, we review these recent genomic discoveries, focusing on acquired DNA repair defects in lymphoma. In addition, we highlight recently identified actionable molecular vulnerabilities associated with recurrent mutations in chronic lymphocytic leukemia (CLL), which serves as a model entity. RECENT FINDINGS: The results of several large lymphoma genome sequencing projects have recently been reported, including CLL, T-PLL and DLBCL. We align these discoveries with proposed mechanisms of mutation acquisition in B-cell lymphomas. Moreover, novel autochthonous mouse models of CLL have recently been generated and we discuss how these models serve as preclinical tools to drive the development of novel targeted therapeutic interventions. Lastly, we highlight the results of early clinical data on novel compounds targeting defects in the DNA damage response of CLL with a particular focus on deleterious ATM mutations. SUMMARY: Defects in DNA repair pathways are selected events in cancer, including lymphomas. Specifically, ATM deficiency is associated with PARP1- and DNA-PKcs inhibitor sensitivity in vitro and in vivo.
    Keywords: Dna Damage -- Research ; Lymphomas -- Genetic Aspects ; Lymphomas -- Research ; Lymphomas -- Development And Progression ; Cellular Signal Transduction -- Research;
    ISSN: 1065-6251
    E-ISSN: 15317048
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  • 6
    Language: English
    In: Cancer discovery, May 2014, Vol.4(5), pp.592-605
    Description: Here, we use a large-scale cell line-based approach to identify cancer cell-specific mutations that are associated with DNA-dependent protein kinase catalytic subunit (DNA-PKcs) dependence. For this purpose, we profiled the mutational landscape across 1,319 cancer-associated genes of 67 distinct cell lines and identified numerous genes involved in homologous recombination-mediated DNA repair, including BRCA1, BRCA2, ATM, PAXIP, and RAD50, as being associated with non-oncogene addiction to DNA-PKcs. Mutations in the mismatch repair gene MSH3, which have been reported to occur recurrently in numerous human cancer entities, emerged as the most significant predictors of DNA-PKcs addiction. Concordantly, DNA-PKcs inhibition robustly induced apoptosis in MSH3-mutant cell lines in vitro and displayed remarkable single-agent efficacy against MSH3-mutant tumors in vivo. Thus, we here identify a therapeutically actionable synthetic lethal interaction between MSH3 and the non-homologous end joining kinase DNA-PKcs. Our observations recommend DNA-PKcs inhibition as a therapeutic concept for the treatment of human cancers displaying homologous recombination defects.
    Keywords: Colonic Neoplasms -- Drug Therapy ; DNA-Activated Protein Kinase -- Antagonists & Inhibitors ; DNA-Binding Proteins -- Genetics ; Nuclear Proteins -- Antagonists & Inhibitors
    ISSN: 21598274
    E-ISSN: 2159-8290
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  • 7
    Language: English
    In: Cell Reports, 23 October 2018, Vol.25(4), pp.1027-1039.e6
    Description: , which encodes p21, functions as a major route for p53-mediated cell-cycle arrest. However, the consequence of gene dosage on tumor suppression has not been systematically investigated. Here, we employed BAC transgenesis to generate a mouse, which harbors an additional allele within its natural genomic context. We show that these mice display enhanced cell-cycle arrest and reduced apoptosis in response to genotoxic stress. Furthermore, using a chemically induced skin cancer model and an autochthonous -driven lung adenocarcinoma model, we show that mice display a cancer protection phenotype that is indistinguishable from that observed in animals. Moreover, we demonstrate that and cooperate in mediating cancer resistance, using a chemically induced fibrosarcoma model. Overall, our allele enabled us to assess the contribution of to -mediated tumor suppression. Torgovnick et al. create a mouse model, carrying a third copy of (p21), which shows enhanced cell-cycle arrest capacity and protection against DNA damage-induced apoptosis. The animals display delayed epithelial regeneration and a robust cancer resistance phenotype, highlighting the importance of p21 in p53-dependent tumor suppression.
    Keywords: Cdkn1a ; P21 ; P53 ; Mouse Model ; Cancer ; Tumor Suppressor ; Cell Cycle Arrest ; Apoptosis ; Cancer Protection ; Biology
    ISSN: 2211-1247
    E-ISSN: 2211-1247
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  • 8
    Language: English
    In: Nat Commun, 2017, Vol.8(1), pp.153-153
    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.
    Keywords: Disease Models, Animal ; Ataxia Telangiectasia Mutated Proteins -- Metabolism ; Leukemia, Lymphocytic, Chronic, B-Cell -- Metabolism ; Poly (Adp-Ribose) Polymerase-1 -- Metabolism ; Tumor Suppressor Protein P53 -- Metabolism;
    ISSN: 2041-1723
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  • 9
    Language: English
    In: Blood, 02 June 2016, Vol.127(22), pp.2732-41
    Description: The adaptor protein MYD88 is critical for relaying activation of Toll-like receptor signaling to NF-κB activation. MYD88 mutations, particularly the p.L265P mutation, have been described in numerous distinct B-cell malignancies, including diffuse large B-cell lymphoma (DLBCL). Twenty-nine percent of activated B-cell-type DLBCL (ABC-DLBCL), which is characterized by constitutive activation of the NF-κB pathway, carry the p.L265P mutation. In addition, ABC-DLBCL frequently displays focal copy number gains affecting BCL2 Here, we generated a novel mouse model in which Cre-mediated recombination, specifically in B cells, leads to the conditional expression of Myd88(p.L252P) (the orthologous position of the human MYD88(p.L265P) mutation) from the endogenous locus. These mice develop a lymphoproliferative disease and occasional transformation into clonal lymphomas. The clonal disease displays the morphologic and immunophenotypical characteristics of ABC-DLBCL. Lymphomagenesis can be accelerated by crossing in a further novel allele, which mediates conditional overexpression of BCL2 Cross-validation experiments in human DLBCL samples revealed that both MYD88 and CD79B mutations are substantially enriched in ABC-DLBCL compared with germinal center B-cell DLBCL. Furthermore, analyses of human DLBCL genome sequencing data confirmed that BCL2 amplifications frequently co-occurred with MYD88 mutations, further validating our approach. Finally, in silico experiments revealed that MYD88-mutant ABC-DLBCL cells in particular display an actionable addiction to BCL2. Altogether, we generated a novel autochthonous mouse model of ABC-DLBCL that could be used as a preclinical platform for the development and validation of novel therapeutic approaches for the treatment of ABC-DLBCL.
    Keywords: Mutation, Missense ; B-Lymphocytes -- Metabolism ; Cell Transformation, Neoplastic -- Metabolism ; Lymphoma, Large B-Cell, Diffuse -- Metabolism ; Myeloid Differentiation Factor 88 -- Biosynthesis ; Neoplasms, Experimental -- Metabolism
    ISSN: 00064971
    E-ISSN: 1528-0020
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  • 10
    In: Theranostics, 2019, Vol.9(21), p.6047-6062
    Description: Extracellular vesicles released by tumor cells contribute to the reprogramming of the tumor microenvironment and interfere with hallmarks of cancer including metastasis. Notably, melanoma cell-derived EVs are able to establish a pre-metastatic niche in distant organs, or on the contrary, exert anti-tumor activity. However, molecular insights into how vesicles are selectively packaged with cargo defining their specific functions remain elusive. Methods : Here, we investigated the role of the chaperone Bcl2-associated anthogene 6 (BAG6, synonym Bat3) for the formation of pro- and anti-tumor EVs. EVs collected from wildtype cells and BAG6-deficient cells were characterized by mass spectrometry and RNAseq. Their tumorigenic potential was analyzed using the B-16V transplantation mouse melanoma model. Results : We demonstrate that EVs from B-16V cells inhibit lung metastasis associated with the mobilization of Ly6C low patrolling monocytes. The formation of these anti-tumor-EVs was dependent on acetylation of p53 by the BAG6/CBP/p300-acetylase complex, followed by recruitment of components of the endosomal sorting complexes required for transport (ESCRT) via a P(S/T)AP double motif of BAG6. Genetic ablation of BAG6 and disruption of this pathway led to the release of a distinct EV subtype, which failed to suppress metastasis but recruited tumor-promoting neutrophils to the pre-metastatic niche. Conclusion : We conclude that the BAG6/CBP/p300-p53 axis is a key pathway directing EV cargo loading and thus a potential novel microenvironmental therapeutic target.
    Keywords: Research Paper ; Extracellular Vesicles ; Exosomes ; Bag6/Cbp/P300-P53 ; Metastasis ; Melanoma
    E-ISSN: 1838-7640
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