Limiting Thymic Precursor Supply Increases the Risk of Lymphoid Malignancy in Murine X-Linked Severe Combined Immunodeficiency

Samantha L. Ginn; Claus V. Hallwirth; Sophia H.Y. Liao; Erdahl T. Teber; Jonathan W. Arthur; Jianmin Wu; Hong Ching Lee; Szun S. Tay; Min Hu; Roger R. Reddel; Matthew P. McCormack; Adrian J. Thrasher; Marina Cavazzana; Stephen I. Alexander; Ian E. Alexander

Molecular Therapy: Nucleic Acids (Mar 2017)

Limiting Thymic Precursor Supply Increases the Risk of Lymphoid Malignancy in Murine X-Linked Severe Combined Immunodeficiency

Samantha L. Ginn,
Claus V. Hallwirth,
Sophia H.Y. Liao,
Erdahl T. Teber,
Jonathan W. Arthur,
Jianmin Wu,
Hong Ching Lee,
Szun S. Tay,
Min Hu,
Roger R. Reddel,
Matthew P. McCormack,
Adrian J. Thrasher,
Marina Cavazzana,
Stephen I. Alexander,
Ian E. Alexander

Affiliations

Samantha L. Ginn: Gene Therapy Research Unit, Children’s Medical Research Institute, The University of Sydney and The Sydney Children’s Hospitals Network, Westmead, NSW 2145, Australia
Claus V. Hallwirth: Gene Therapy Research Unit, Children’s Medical Research Institute, The University of Sydney and The Sydney Children’s Hospitals Network, Westmead, NSW 2145, Australia
Sophia H.Y. Liao: Gene Therapy Research Unit, Children’s Medical Research Institute, The University of Sydney and The Sydney Children’s Hospitals Network, Westmead, NSW 2145, Australia
Erdahl T. Teber: Bioinformatics Unit, Children’s Medical Research Institute, The University of Sydney, Westmead, NSW 2145, Australia
Jonathan W. Arthur: Bioinformatics Unit, Children’s Medical Research Institute, The University of Sydney, Westmead, NSW 2145, Australia
Jianmin Wu: Kinghorn Cancer Centre & Cancer Division, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia; St Vincent’s Clinical School, University of New South Wales, Darlinghurst, NSW 2010, Australia
Hong Ching Lee: Kinghorn Cancer Centre & Cancer Division, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia; St Vincent’s Clinical School, University of New South Wales, Darlinghurst, NSW 2010, Australia
Szun S. Tay: Gene Therapy Research Unit, Children’s Medical Research Institute, The University of Sydney and The Sydney Children’s Hospitals Network, Westmead, NSW 2145, Australia
Min Hu: Centre for Kidney Research of The Children’s Hospital at Westmead, Westmead, NSW 2145, Australia
Roger R. Reddel: Cancer Research Unit, Children’s Medical Research Institute, The University of Sydney, Westmead, NSW 2145, Australia
Matthew P. McCormack: Australian Centre for Blood Diseases, Monash University, Melbourne, VIC 3800, Australia
Adrian J. Thrasher: Infection, Immunity, Inflammation, UCL Great Ormond Street Institute of Child Health, London WC1N 1EH, UK
Marina Cavazzana: Department of Biotherapy, Hôpital Necker-Enfants Malades, Paris 75015, France
Stephen I. Alexander: Centre for Kidney Research of The Children’s Hospital at Westmead, Westmead, NSW 2145, Australia; Discipline of Child and Adolescent Health, The University of Sydney, Westmead, NSW 2145, Australia
Ian E. Alexander: Gene Therapy Research Unit, Children’s Medical Research Institute, The University of Sydney and The Sydney Children’s Hospitals Network, Westmead, NSW 2145, Australia; Discipline of Child and Adolescent Health, The University of Sydney, Westmead, NSW 2145, Australia; Corresponding author: Professor Ian E. Alexander, Gene Therapy Research Unit, The Children’s Hospital at Westmead, Locked Bag 4001, Westmead, NSW 2145, Australia.

Journal volume & issue: Vol. 6
pp. 1 – 14

Abstract

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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 Notch1 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. Keywords: lymphomagenesis, gene therapy, primary immune deficiency, SCID-X1, self-renewal, thymus

Published in Molecular Therapy: Nucleic Acids

ISSN: 2162-2531 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: https://www.cell.com/molecular-therapy-family/nucleic-acids/latest-content

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