Limiting Thymic Precursor Supply Increases the Risk of Lymphoid Malignancy in Murine X-Linked Severe Combined Immunodeficiency.
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.
Gene Therapy Research Unit, Children's Medical Research Institute, The University of Sydney and The Sydney Children's Hospitals Network, Westmead, NSW 2145, Australia.
Samantha L
SL
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
CV
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
SHY
Liao
Bioinformatics Unit, Children's Medical Research Institute, The University of Sydney, Westmead, NSW 2145, Australia.
Erdahl T
ET
Teber
Bioinformatics Unit, Children's Medical Research Institute, The University of Sydney, Westmead, NSW 2145, Australia.
Jonathan W
JW
Arthur
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.
Jianmin
J
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
HC
Lee
Gene Therapy Research Unit, Children's Medical Research Institute, The University of Sydney and The Sydney Children's Hospitals Network, Westmead, NSW 2145, Australia.
Szun S
SS
Tay
Centre for Kidney Research of The Children's Hospital at Westmead, Westmead, NSW 2145, Australia.
Min
M
Hu
Cancer Research Unit, Children's Medical Research Institute, The University of Sydney, Westmead, NSW 2145, Australia.
Roger R
RR
Reddel
Australian Centre for Blood Diseases, Monash University, Melbourne, VIC 3800, Australia.
Matthew P
MP
McCormack
Infection, Immunity, Inflammation, UCL Great Ormond Street Institute of Child Health, London WC1N 1EH, UK.
Adrian J
AJ
Thrasher
Department of Biotherapy, Hôpital Necker-Enfants Malades, Paris 75015, France.
Marina
M
Cavazzana
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.
Stephen I
SI
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. Electronic address: ian.alexander@health.nsw.gov.au.
Ian E
IE
Alexander
SCID-X1; gene therapy; lymphomagenesis; primary immune deficiency; self-renewal; thymus