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  • 1
    Abstract: Playing a central role in both innate and adaptive immunity, CD4(+) T cells are a key target for genetic modifications in basic research and immunotherapy. In this article, we describe novel lentiviral vectors (CD4-LV) that have been rendered selective for human or simian CD4(+) cells by surface engineering. When applied to PBMCs, CD4-LV transduced CD4(+) but not CD4(-) cells. Notably, also unstimulated T cells were stably genetically modified. Upon systemic or intrasplenic administration into mice reconstituted with human PBMCs or hematopoietic stem cells, reporter gene expression was predominantly detected in lymphoid organs. Evaluation of GFP expression in organ-derived cells and blood by flow cytometry demonstrated exclusive gene transfer into CD4(+) human lymphocytes. In bone marrow and spleen, memory T cells were preferentially hit. Toward therapeutic applications, we also show that CD4-LV can be used for HIV gene therapy, as well as for tumor therapy, by delivering chimeric Ag receptors. The potential for in vivo delivery of the FOXP3 gene was also demonstrated, making CD4-LV a powerful tool for inducible regulatory T cell generation. In summary, our work demonstrates the exclusive gene transfer into a T cell subset upon systemic vector administration opening an avenue toward novel strategies in immunotherapy.
    Type of Publication: Journal article published
    PubMed ID: 26232436
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  • 2
    Abstract: Survival rates after allogeneic hematopoietic cell transplantation (HCT) for Fanconi anemia (FA) have increased dramatically since 2000. However, the use of autologous stem cell gene therapy, whereby the patient's own blood stem cells are modified to express the wild-type gene product, could potentially avoid the early and late complications of allogeneic HCT. Over the last decades, gene therapy has experienced a high degree of optimism interrupted by periods of diminished expectation. Optimism stems from recent examples of successful gene correction in several congenital immunodeficiencies, whereas diminished expectations come from the realization that gene therapy will not be free of side effects. The goal of the 1st International Fanconi Anemia Gene Therapy Working Group Meeting was to determine the optimal strategy for moving stem cell gene therapy into clinical trials for individuals with FA. To this end, key investigators examined vector design, transduction method, criteria for large-scale clinical-grade vector manufacture, hematopoietic cell preparation, and eligibility criteria for FA patients most likely to benefit. The report summarizes the roadmap for the development of gene therapy for FA.
    Type of Publication: Journal article published
    PubMed ID: 21540837
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  • 3
    Type of Publication: Journal article published
    PubMed ID: 22248350
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  • 4
    Publication Date: 2018-08-03
    Description: Activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL) is an aggressive lymphoproliferative disorder involving chronic NF-B activation. Several mutations in the BCR and MyD88 signaling pathway components, such as MyD88 L265P, are implicated in this aberrant activation. Among heat shock proteins, HSP110 has recently been identified as a prosurvival and/or proliferation factor in many cancers, but its role in ABC-DLBCL survival mechanisms remained to be established. We observed that short hairpin RNA–mediated HSP110 silencing decreased the survival of several ABC-DLBCL cell lines and decreased immunoglobulin M-MyD88 co-localization and subsequent NF-B signaling. Conversely, overexpression of HSP110 in ABC-DLBCL or non-DLBCL cell lines increased NF-B signaling, indicating a tight interplay between HSP110 and the NF-B pathway. By using immunoprecipitation and proximity ligation assays, we identified an interaction between HSP110 and both wild-type MyD88 and MyD88 L265P. HSP110 stabilized both MyD88 forms with a stronger effect on MyD88 L265P, thus facilitating chronic NF-B activation. Finally, HSP110 expression was higher in lymph node biopsies from patients with ABC-DLBCL than in normal reactive lymph nodes, and a strong correlation was found between the level of HSP110 and MyD88. In conclusion, we identified HSP110 as a regulator of NF-B signaling through MyD88 stabilization in ABC-DLBCL. This finding reveals HSP110 as a new potential therapeutic target in ABC-DLBCL.
    Keywords: Lymphoid Neoplasia
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
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  • 5
    Publication Date: 2015-09-04
    Description: Whether cancer is maintained by a small number of stem cells or is composed of proliferating cells with approximate phenotypic equivalency is a central question in cancer biology. In the stem cell hypothesis, relapse after treatment may occur by failure to eradicate cancer stem cells. Chronic myeloid leukaemia (CML) is quintessential to this hypothesis. CML is a myeloproliferative disorder that results from dysregulated tyrosine kinase activity of the fusion oncoprotein BCR-ABL. During the chronic phase, this sole genetic abnormality (chromosomal translocation Ph(+): t(9;22)(q34;q11)) at the stem cell level causes increased proliferation of myeloid cells without loss of their capacity to differentiate. Without treatment, most patients progress to the blast phase when additional oncogenic mutations result in a fatal acute leukaemia made of proliferating immature cells. Imatinib mesylate and other tyrosine kinase inhibitors (TKIs) that target the kinase activity of BCR-ABL have improved patient survival markedly. However, fewer than 10% of patients reach the stage of complete molecular response (CMR), defined as the point when BCR-ABL transcripts become undetectable in blood cells. Failure to reach CMR results from the inability of TKIs to eradicate quiescent CML leukaemia stem cells (LSCs). Here we show that the residual CML LSC pool can be gradually purged by the glitazones, antidiabetic drugs that are agonists of peroxisome proliferator-activated receptor-gamma (PPARgamma). We found that activation of PPARgamma by the glitazones decreases expression of STAT5 and its downstream targets HIF2alpha and CITED2, which are key guardians of the quiescence and stemness of CML LSCs. When pioglitazone was given temporarily to three CML patients in chronic residual disease in spite of continuous treatment with imatinib, all of them achieved sustained CMR, up to 4.7 years after withdrawal of pioglitazone. This suggests that clinically relevant cancer eradication may become a generally attainable goal by combination therapy that erodes the cancer stem cell pool.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Prost, Stephane -- Relouzat, Francis -- Spentchian, Marc -- Ouzegdouh, Yasmine -- Saliba, Joseph -- Massonnet, Gerald -- Beressi, Jean-Paul -- Verhoeyen, Els -- Raggueneau, Victoria -- Maneglier, Benjamin -- Castaigne, Sylvie -- Chomienne, Christine -- Chretien, Stany -- Rousselot, Philippe -- Leboulch, Philippe -- England -- Nature. 2015 Sep 17;525(7569):380-3. doi: 10.1038/nature15248. Epub 2015 Sep 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉CEA, Institute of Emerging Diseases and Innovative Therapies (iMETI), F-92265 Fontenay-aux-Roses, France. ; Departement de biologie medicale, Hopital Mignot, F-78150 Le Chesnay, France. ; Unite de Biologie Cellulaire, UMR-S-940 Institut Universitaire d'Hematologie, Hopital Saint Louis, F-75010 Paris, France. ; Service d'Endocrinologie et de Diabetologie, Hopital Mignot, F-78150 Le Chesnay, France. ; CIRI, International Center for Infectiology Research, EVIR team, Inserm, U1111, CNRS, UMR5308, Universite de Lyon-1, ENS de Lyon, 69007 Lyon, France. ; Inserm, U895, Centre de Medecine Moleculaire (C3M), equipe 3, 06204 Nice, France. ; Laboratoire d'hematologie, Centre Hospitalier de Versailles, F-78150 Le Chesnay, France. ; Unite de Pharmacologie, Service de Biologie Medicale, Centre Hospitalier de Versailles, F-78150 Le Chesnay, France. ; Service d'Hematologie et d'Oncologie, Hopital Mignot, Universite Versailles Saint-Quentin-en-Yvelines, F-78150 Le Chesnay, France. ; Inserm, Institute of Emerging Diseases and Innovative Therapies (iMETI), F-92265 Fontenay-aux-Roses, France. ; Genetics Division, Brigham &Women's Hospital and Harvard Medical School, Boston, Massachussetts 02115, USA. ; Hematology Division, Ramathibodi Hospital and Mahidol University, 10400 Bangkok, Thailand.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="" target="_blank"〉PubMed〈/a〉
    Keywords: Antineoplastic Combined Chemotherapy Protocols/administration & ; dosage/*pharmacology/*therapeutic use ; Basic Helix-Loop-Helix Transcription Factors/metabolism ; Benzamides/*administration & dosage/pharmacology/therapeutic use ; Cell Proliferation ; Gene Expression Regulation, Neoplastic ; Humans ; Imatinib Mesylate ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/*drug ; therapy/genetics/metabolism/*pathology ; Neoplastic Stem Cells/*drug effects/metabolism/pathology ; PPAR gamma/*agonists/metabolism ; Piperazines/*administration & dosage/pharmacology/therapeutic use ; Pyrimidines/*administration & dosage/pharmacology/therapeutic use ; Repressor Proteins/metabolism ; STAT5 Transcription Factor/metabolism ; Thiazolidinediones/*administration & dosage/pharmacology/therapeutic use ; Trans-Activators/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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