Limiting Thymic Precursor Supply Increases the Risk of Lymphoid Malignancy in Murine X-Linked Severe Combined Immunodeficiency
Identifieur interne : 001B89 ( Main/Exploration ); précédent : 001B88; suivant : 001B90Limiting Thymic Precursor Supply Increases the Risk of Lymphoid Malignancy in Murine X-Linked Severe Combined Immunodeficiency
Auteurs : Samantha L. Ginn [Australie] ; Claus V. Hallwirth [Australie] ; Sophia H. Y. Liao [Australie] ; Erdahl T. Teber [Australie] ; Jonathan W. Arthur [Australie] ; Jianmin Wu [Australie] ; Hong Ching Lee [Australie] ; Szun S. Tay [Australie] ; Min Hu [Australie] ; Roger R. Reddel [Australie] ; Matthew P. Mccormack [Australie] ; Adrian J. Thrasher [Royaume-Uni] ; Marina Cavazzana [France] ; Stephen I. Alexander [Australie] ; Ian E. Alexander [Australie]Source :
- Molecular Therapy. Nucleic Acids [ 2162-2531 ] ; 2016.
Abstract
In early gene therapy trials for SCID-X1, using γ-retroviral vectors, T cell leukemias developed in a subset of patients secondary to insertional proto-oncogene activation. In contrast, we have reported development of T cell leukemias in SCID-X1 mice following lentivirus-mediated gene therapy independent of insertional mutagenesis. A distinguishing feature in our study was that only a proportion of transplanted γc-deficient progenitors were transduced and therefore competent for reconstitution. We hypothesized that reconstitution of SCID-X1 mice with limiting numbers of hematopoietic progenitors might be a risk factor for lymphoid malignancy. To test this hypothesis, in the absence of transduction, SCID-X1 mice were reconstituted with serially fewer wild-type hematopoietic progenitors. A robust inverse correlation between hematopoietic progenitor cell dose and T-lymphoid malignancy was observed, with earlier disease onset at lower cell doses. Malignancies were of donor origin and carried activating
Url:
DOI: 10.1016/j.omtn.2016.11.011
PubMed: 28325276
PubMed Central: 5363493
Affiliations:
- Australie, France, Royaume-Uni
- Nouvelle-Galles du Sud, Île-de-France
- Paris, Sydney
- Université de Sydney
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Ginn</name><affiliation wicri:level="1"><nlm:aff id="aff1">Gene Therapy Research Unit, Children’s Medical Research Institute, The University of Sydney and The Sydney Children’s Hospitals Network, Westmead, NSW 2145, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Gene Therapy Research Unit, Children’s Medical Research Institute, The University of Sydney and The Sydney Children’s Hospitals Network, Westmead, NSW 2145</wicri:regionArea><wicri:noRegion>NSW 2145</wicri:noRegion></affiliation></author><author><name sortKey="Hallwirth, Claus V" sort="Hallwirth, Claus V" uniqKey="Hallwirth C" first="Claus V." last="Hallwirth">Claus V. Hallwirth</name><affiliation wicri:level="1"><nlm:aff id="aff1">Gene Therapy Research Unit, Children’s Medical Research Institute, The University of Sydney and The Sydney Children’s Hospitals Network, Westmead, NSW 2145, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Gene Therapy Research Unit, Children’s Medical Research Institute, The University of Sydney and The Sydney Children’s Hospitals Network, Westmead, NSW 2145</wicri:regionArea><wicri:noRegion>NSW 2145</wicri:noRegion></affiliation></author><author><name sortKey="Liao, Sophia H Y" sort="Liao, Sophia H Y" uniqKey="Liao S" first="Sophia H. Y." last="Liao">Sophia H. Y. Liao</name><affiliation wicri:level="1"><nlm:aff id="aff1">Gene Therapy Research Unit, Children’s Medical Research Institute, The University of Sydney and The Sydney Children’s Hospitals Network, Westmead, NSW 2145, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Gene Therapy Research Unit, Children’s Medical Research Institute, The University of Sydney and The Sydney Children’s Hospitals Network, Westmead, NSW 2145</wicri:regionArea><wicri:noRegion>NSW 2145</wicri:noRegion></affiliation></author><author><name sortKey="Teber, Erdahl T" sort="Teber, Erdahl T" uniqKey="Teber E" first="Erdahl T." last="Teber">Erdahl T. Teber</name><affiliation wicri:level="4"><nlm:aff id="aff2">Bioinformatics Unit, Children’s Medical Research Institute, The University of Sydney, Westmead, NSW 2145, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Bioinformatics Unit, Children’s Medical Research Institute, The University of Sydney, Westmead, NSW 2145</wicri:regionArea><orgName type="university">Université de Sydney</orgName><placeName><settlement type="city">Sydney</settlement><region type="état">Nouvelle-Galles du Sud</region></placeName></affiliation></author><author><name sortKey="Arthur, Jonathan W" sort="Arthur, Jonathan W" uniqKey="Arthur J" first="Jonathan W." last="Arthur">Jonathan W. Arthur</name><affiliation wicri:level="4"><nlm:aff id="aff2">Bioinformatics Unit, Children’s Medical Research Institute, The University of Sydney, Westmead, NSW 2145, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Bioinformatics Unit, Children’s Medical Research Institute, The University of Sydney, Westmead, NSW 2145</wicri:regionArea><orgName type="university">Université de Sydney</orgName><placeName><settlement type="city">Sydney</settlement><region type="état">Nouvelle-Galles du Sud</region></placeName></affiliation></author><author><name sortKey="Wu, Jianmin" sort="Wu, Jianmin" uniqKey="Wu J" first="Jianmin" last="Wu">Jianmin Wu</name><affiliation wicri:level="1"><nlm:aff id="aff3">Kinghorn Cancer Centre & Cancer Division, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Kinghorn Cancer Centre & Cancer Division, Garvan Institute of Medical Research, Darlinghurst, NSW 2010</wicri:regionArea><wicri:noRegion>NSW 2010</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="aff4">St Vincent’s Clinical School, University of New South Wales, Darlinghurst, NSW 2010, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>St Vincent’s Clinical School, University of New South Wales, Darlinghurst, NSW 2010</wicri:regionArea><wicri:noRegion>NSW 2010</wicri:noRegion></affiliation></author><author><name sortKey="Lee, Hong Ching" sort="Lee, Hong Ching" uniqKey="Lee H" first="Hong Ching" last="Lee">Hong Ching Lee</name><affiliation wicri:level="1"><nlm:aff id="aff3">Kinghorn Cancer Centre & Cancer Division, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Kinghorn Cancer Centre & Cancer Division, Garvan Institute of Medical Research, Darlinghurst, NSW 2010</wicri:regionArea><wicri:noRegion>NSW 2010</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="aff4">St Vincent’s Clinical School, University of New South Wales, Darlinghurst, NSW 2010, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>St Vincent’s Clinical School, University of New South Wales, Darlinghurst, NSW 2010</wicri:regionArea><wicri:noRegion>NSW 2010</wicri:noRegion></affiliation></author><author><name sortKey="Tay, Szun S" sort="Tay, Szun S" uniqKey="Tay S" first="Szun S." last="Tay">Szun S. Tay</name><affiliation wicri:level="1"><nlm:aff id="aff1">Gene Therapy Research Unit, Children’s Medical Research Institute, The University of Sydney and The Sydney Children’s Hospitals Network, Westmead, NSW 2145, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Gene Therapy Research Unit, Children’s Medical Research Institute, The University of Sydney and The Sydney Children’s Hospitals Network, Westmead, NSW 2145</wicri:regionArea><wicri:noRegion>NSW 2145</wicri:noRegion></affiliation></author><author><name sortKey="Hu, Min" sort="Hu, Min" uniqKey="Hu M" first="Min" last="Hu">Min Hu</name><affiliation wicri:level="1"><nlm:aff id="aff5">Centre for Kidney Research of The Children’s Hospital at Westmead, Westmead, NSW 2145, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Centre for Kidney Research of The Children’s Hospital at Westmead, Westmead, NSW 2145</wicri:regionArea><wicri:noRegion>NSW 2145</wicri:noRegion></affiliation></author><author><name sortKey="Reddel, Roger R" sort="Reddel, Roger R" uniqKey="Reddel R" first="Roger R." last="Reddel">Roger R. Reddel</name><affiliation wicri:level="4"><nlm:aff id="aff6">Cancer Research Unit, Children’s Medical Research Institute, The University of Sydney, Westmead, NSW 2145, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Cancer Research Unit, Children’s Medical Research Institute, The University of Sydney, Westmead, NSW 2145</wicri:regionArea><orgName type="university">Université de Sydney</orgName><placeName><settlement type="city">Sydney</settlement><region type="état">Nouvelle-Galles du Sud</region></placeName></affiliation></author><author><name sortKey="Mccormack, Matthew P" sort="Mccormack, Matthew P" uniqKey="Mccormack M" first="Matthew P." last="Mccormack">Matthew P. Mccormack</name><affiliation wicri:level="1"><nlm:aff id="aff7">Australian Centre for Blood Diseases, Monash University, Melbourne, VIC 3800, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Australian Centre for Blood Diseases, Monash University, Melbourne, VIC 3800</wicri:regionArea><wicri:noRegion>VIC 3800</wicri:noRegion></affiliation></author><author><name sortKey="Thrasher, Adrian J" sort="Thrasher, Adrian J" uniqKey="Thrasher A" first="Adrian J." last="Thrasher">Adrian J. Thrasher</name><affiliation wicri:level="1"><nlm:aff id="aff8">Infection, Immunity, Inflammation, UCL Great Ormond Street Institute of Child Health, London WC1N 1EH, UK</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Infection, Immunity, Inflammation, UCL Great Ormond Street Institute of Child Health, London WC1N 1EH</wicri:regionArea><wicri:noRegion>London WC1N 1EH</wicri:noRegion></affiliation></author><author><name sortKey="Cavazzana, Marina" sort="Cavazzana, Marina" uniqKey="Cavazzana M" first="Marina" last="Cavazzana">Marina Cavazzana</name><affiliation wicri:level="1"><nlm:aff id="aff9">Department of Biotherapy, Hôpital Necker-Enfants Malades, Paris 75015, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Department of Biotherapy, Hôpital Necker-Enfants Malades, Paris 75015</wicri:regionArea><wicri:noRegion>75015</wicri:noRegion><placeName><settlement type="city">Paris</settlement><region type="région" nuts="2">Île-de-France</region></placeName></affiliation></author><author><name sortKey="Alexander, Stephen I" sort="Alexander, Stephen I" uniqKey="Alexander S" first="Stephen I." last="Alexander">Stephen I. Alexander</name><affiliation wicri:level="1"><nlm:aff id="aff5">Centre for Kidney Research of The Children’s Hospital at Westmead, Westmead, NSW 2145, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Centre for Kidney Research of The Children’s Hospital at Westmead, Westmead, NSW 2145</wicri:regionArea><wicri:noRegion>NSW 2145</wicri:noRegion></affiliation><affiliation wicri:level="4"><nlm:aff id="aff10">Discipline of Child and Adolescent Health, The University of Sydney, Westmead, NSW 2145, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Discipline of Child and Adolescent Health, The University of Sydney, Westmead, NSW 2145</wicri:regionArea><orgName type="university">Université de Sydney</orgName><placeName><settlement type="city">Sydney</settlement><region type="état">Nouvelle-Galles du Sud</region></placeName></affiliation></author><author><name sortKey="Alexander, Ian E" sort="Alexander, Ian E" uniqKey="Alexander I" first="Ian E." last="Alexander">Ian E. Alexander</name><affiliation wicri:level="1"><nlm:aff id="aff1">Gene Therapy Research Unit, Children’s Medical Research Institute, The University of Sydney and The Sydney Children’s Hospitals Network, Westmead, NSW 2145, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Gene Therapy Research Unit, Children’s Medical Research Institute, The University of Sydney and The Sydney Children’s Hospitals Network, Westmead, NSW 2145</wicri:regionArea><wicri:noRegion>NSW 2145</wicri:noRegion></affiliation><affiliation wicri:level="4"><nlm:aff id="aff10">Discipline of Child and Adolescent Health, The University of Sydney, Westmead, NSW 2145, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Discipline of Child and Adolescent Health, The University of Sydney, Westmead, NSW 2145</wicri:regionArea><orgName type="university">Université de Sydney</orgName><placeName><settlement type="city">Sydney</settlement><region type="état">Nouvelle-Galles du Sud</region></placeName></affiliation></author></analytic><series><title level="j">Molecular Therapy. Nucleic Acids</title><idno type="eISSN">2162-2531</idno><imprint><date when="2016">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>In early gene therapy trials for SCID-X1, using γ-retroviral vectors, T cell leukemias developed in a subset of patients secondary to insertional proto-oncogene activation. In contrast, we have reported development of T cell leukemias in SCID-X1 mice following lentivirus-mediated gene therapy independent of insertional mutagenesis. A distinguishing feature in our study was that only a proportion of transplanted γc-deficient progenitors were transduced and therefore competent for reconstitution. We hypothesized that reconstitution of SCID-X1 mice with limiting numbers of hematopoietic progenitors might be a risk factor for lymphoid malignancy. To test this hypothesis, in the absence of transduction, SCID-X1 mice were reconstituted with serially fewer wild-type hematopoietic progenitors. A robust inverse correlation between hematopoietic progenitor cell dose and T-lymphoid malignancy was observed, with earlier disease onset at lower cell doses. Malignancies were of donor origin and carried activating <italic>Notch1</italic> mutations. These findings align with emerging evidence that thymocyte self-renewal induced by progenitor deprivation carries an oncogenic risk that is modulated by intra-thymic competition from differentiation-committed cells. Although insertional proto-oncogene activation is required for the development of malignancy in humans, failure of γc-deficient thymocytes to effectively compete with this at-risk cell population may have also contributed to oncogenesis observed in early SCID-X1 trials.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Cavazzana Calvo, M" uniqKey="Cavazzana Calvo M">M. Cavazzana-Calvo</name></author><author><name sortKey="Hacein Bey, S" uniqKey="Hacein Bey S">S. Hacein-Bey</name></author><author><name sortKey="De Saint Basile, G" uniqKey="De Saint Basile G">G. de Saint Basile</name></author><author><name sortKey="Gross, F" uniqKey="Gross F">F. Gross</name></author><author><name sortKey="Yvon, E" uniqKey="Yvon E">E. Yvon</name></author><author><name sortKey="Nusbaum, P" uniqKey="Nusbaum P">P. Nusbaum</name></author><author><name sortKey="Selz, F" uniqKey="Selz F">F. 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Ginn</name></noRegion><name sortKey="Alexander, Ian E" sort="Alexander, Ian E" uniqKey="Alexander I" first="Ian E." last="Alexander">Ian E. Alexander</name><name sortKey="Alexander, Ian E" sort="Alexander, Ian E" uniqKey="Alexander I" first="Ian E." last="Alexander">Ian E. Alexander</name><name sortKey="Alexander, Stephen I" sort="Alexander, Stephen I" uniqKey="Alexander S" first="Stephen I." last="Alexander">Stephen I. Alexander</name><name sortKey="Alexander, Stephen I" sort="Alexander, Stephen I" uniqKey="Alexander S" first="Stephen I." last="Alexander">Stephen I. Alexander</name><name sortKey="Arthur, Jonathan W" sort="Arthur, Jonathan W" uniqKey="Arthur J" first="Jonathan W." last="Arthur">Jonathan W. Arthur</name><name sortKey="Hallwirth, Claus V" sort="Hallwirth, Claus V" uniqKey="Hallwirth C" first="Claus V." last="Hallwirth">Claus V. Hallwirth</name><name sortKey="Hu, Min" sort="Hu, Min" uniqKey="Hu M" first="Min" last="Hu">Min Hu</name><name sortKey="Lee, Hong Ching" sort="Lee, Hong Ching" uniqKey="Lee H" first="Hong Ching" last="Lee">Hong Ching Lee</name><name sortKey="Lee, Hong Ching" sort="Lee, Hong Ching" uniqKey="Lee H" first="Hong Ching" last="Lee">Hong Ching Lee</name><name sortKey="Liao, Sophia H Y" sort="Liao, Sophia H Y" uniqKey="Liao S" first="Sophia H. Y." last="Liao">Sophia H. Y. Liao</name><name sortKey="Mccormack, Matthew P" sort="Mccormack, Matthew P" uniqKey="Mccormack M" first="Matthew P." last="Mccormack">Matthew P. Mccormack</name><name sortKey="Reddel, Roger R" sort="Reddel, Roger R" uniqKey="Reddel R" first="Roger R." last="Reddel">Roger R. Reddel</name><name sortKey="Tay, Szun S" sort="Tay, Szun S" uniqKey="Tay S" first="Szun S." last="Tay">Szun S. Tay</name><name sortKey="Teber, Erdahl T" sort="Teber, Erdahl T" uniqKey="Teber E" first="Erdahl T." last="Teber">Erdahl T. Teber</name><name sortKey="Wu, Jianmin" sort="Wu, Jianmin" uniqKey="Wu J" first="Jianmin" last="Wu">Jianmin Wu</name><name sortKey="Wu, Jianmin" sort="Wu, Jianmin" uniqKey="Wu J" first="Jianmin" last="Wu">Jianmin Wu</name></country><country name="Royaume-Uni"><noRegion><name sortKey="Thrasher, Adrian J" sort="Thrasher, Adrian J" uniqKey="Thrasher A" first="Adrian J." last="Thrasher">Adrian J. Thrasher</name></noRegion></country><country name="France"><region name="Île-de-France"><name sortKey="Cavazzana, Marina" sort="Cavazzana, Marina" uniqKey="Cavazzana M" first="Marina" last="Cavazzana">Marina Cavazzana</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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