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  • IN-VIVO  (2)
  • CANCER  (1)
  • CELL  (1)
  • CELLS  (1)
Keywords
  • 1
    Keywords: CELLS ; tumor ; BLOOD ; CELL ; Germany ; human ; IN-VIVO ; MODEL ; THERAPY ; FOLLOW-UP ; QUANTIFICATION ; LONG-TERM ; GENE ; gene therapy ; TIME ; TRANSDUCTION ; gene transfer ; GENE-TRANSFER ; TRANSPLANTATION ; BIOLOGY ; BREAST-CANCER ; NO ; resistance ; VECTOR ; IMMUNODEFICIENT MICE ; STEM-CELLS ; PROGENITOR CELLS ; POLYMERASE-CHAIN-REACTION ; CHAIN-REACTION ; HEMATOPOIETIC-CELLS ; PERIPHERAL-BLOOD ; MULTIDRUG-RESISTANCE ; RESISTANCE MDR-1 GENE ; retroviral vector ; insertional mutagenesis ; LACKING ; multidrug resistance ; CHAIN ; ONCOLOGY ; THERAPIES ; polymerase chain reaction ; P-GLYCOPROTEIN ; BONE-MARROW-CELLS ; stem cells ; LEVEL ; USA ; progenitor cell ; microbiology ; STEM ; PROGENITOR-CELL ; rhesus macaque ; biotechnology ; CD34+ ; DOMINANCE ; long-term follow-up ; multidrug resistance 1
    Abstract: Previous murine studies have suggested that retroviral multidrug resistance 1 ( MDR1) gene transfer may be associated with a myeloproliferative disorder. Analyses at a clonal level and prolonged long-term follow-up in a model with more direct relevance to human biology were lacking. In this study, we analyzed the contribution of individual CD34selected peripheral blood progenitor cells to long-term rhesus macaque hematopoiesis after transduction with a retroviral vector either expressing the multidrug resistance 1 gene ( HaMDR1 vector) or expressing the neomycin resistance ( NeoR) gene ( G1Na vector). We found a total of 122 contributing clones from 8 weeks up to 4 years after transplantation. One hundred two clones contained the G1Na vector, whereas only 20 clones contained the HaMDR1 vector. Here, we show for the first time realtime polymerase chain reaction based quantification of individual transduced cell clones constituting 0.0008% +/- 0.0003% to 0.0041% +/- 0.00032% of primate peripheral blood cells. No clonal dominance was observed
    Type of Publication: Journal article published
    PubMed ID: 17615269
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  • 2
    Keywords: CANCER ; IN-VITRO ; KINASE ; TYROSINE KINASE ; DISEASE ; resistance ; MUTATIONS ; INTERFERON-ALPHA ; CHRONIC MYELOGENOUS LEUKEMIA ; ORGANIZATION ; IMATINIB MESYLATE ; COMBINATION THERAPY ; CML ; COMPLETE MOLECULAR REMISSION ; DISCONTINUATION ; mathematical modelling
    Abstract: BACKGROUND: Newly diagnosed patients with chronic myeloid leukaemia (CML) are currently treated with tyrosine kinase inhibitors (TKIs) such as imatinib, nilotinib or dasatinib. However, incomplete eradication of residual disease is a general problem of long-term TKI therapy. Activation of mouse haematopoietic stem cells by interferon-alpha (IFN alpha) stimulated the discussion of whether a combination treatment leads to accelerated eradication of the CML clone. METHODS: We base our simulation approach on a mathematical model describing human CML as a competition phenomenon between normal and malignant cells. We amend this model to incorporate the description of IFN alpha activity and simulate different scenarios for potential treatment combinations. RESULTS: We demonstrate that the overall sensitivity of CML stem cells to IFN alpha activation is a crucial determinant for the benefit of a potential combination therapy. We furthermore show that pulsed IFN alpha together with continuous TKI administration is the most promising strategy for a combination treatment in which the therapeutic benefit prevails adverse side effects. CONCLUSION: Our modelling approach is a highly beneficial tool to quantitatively address the competition between normal and leukaemic haematopoiesis in treated CML patients. We derive testable predictions for different experimental settings that are suggested before the clinical implementation of the combination treatment.
    Type of Publication: Journal article published
    PubMed ID: 22538973
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  • 3
    Keywords: IN-VIVO ; PATHWAY ; THERAPY ; MICE ; PATTERNS ; HEMATOPOIETIC-CELLS ; MARROW-REPOPULATING CELLS ; GREEN FLUORESCENT PROTEIN ; insertional mutagenesis ; IN-VIVO SELECTION ; O-6-ALKYLGUANINE-DNA ALKYLTRANSFERASE ; retroviral vector integration ; CHRONIC GRANULOMATOUS-DISEASE ; LARGE-ANIMAL MODEL ; RESISTANCE GENE-THERAPY
    Abstract: Gene transfer of mutant O-6-methylguanine-DNA-methyltransferase (MGMT(P140K)) into hematopoietic stem cells (HSCs) protects hematopoiesis from alkylating agents and allows efficient in vivo selection of transduced HSCs. However, insertional mutagenesis, high regenerative stress associated with selection, and the genotoxic potential of alkylating drugs represent considerable risk factors for clinical applications of this approach. Therefore, we investigated the long-term effect of MGMT(P140K) gene transfer followed by repetitive, dose-intensive treatment with alkylating agents in a murine serial bone marrow transplant model and assessed clonality of hematopoiesis up to tertiary recipients. The substantial selection pressure resulted in almost completely transduced hematopoiesis in all cohorts. Ligation-mediated PCR and next-generation sequencing identified several repopulating clones carrying vector insertions in distinct genomic regions that were similar to 9 kb of size (common integration sites). Beside polyclonal reconstitution in the majority of the mice, we also detected monoclonal or oligoclonal re-population patterns with HSC clones showing vector insertions in the Usp10 or Tubb3 gene. Interestingly, neither Usp10, Tubb3, nor any of the genes located in common integration sites have been linked to clonal expansion in previous preclinical or clinical gene therapy trials. However, a considerable number of these genes are involved in DNA damage response and cell fate decision pathways following cytostatic drug application. Thus, in summary, our study advocates ligation-mediated PCR and next generation sequencing as an effective and reliable method to identify gene products associated with clonal survival in specific experimental settings such as chemoselection using alkylating agents
    Type of Publication: Journal article published
    PubMed ID: 21319998
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