Abstract
Emerging evidence indicates that thymocyte self-renewal induced by progenitor deprivation carries an oncogenic risk that is modulated by intra-thymic competition from differentiation-committed cells. Here we discuss formative studies demonstrating that, in mice, early thymocytes acquire self-renewing potential when thymic progenitor supply is sub-physiological and the importance of cellular competition with this at-risk cell population to prevent lymphoid malignancy. We also consider the possibility that increased thymic residency time, established under conditions of limited cellular competition, may have contributed to oncogenesis observed in early SCID-X1 trials when combined with insertional activation of proto-oncogenes such as LMO2.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Apasov SG, Blackburn MR, Kellems RE, Smith PT, Sitkovsky MV (2001) Adenosine deaminase deficiency increases thymic apoptosis and causes defective T cell receptor signaling. J Clin Investig 108:131–141
Boehm T (2012) Self-renewal of thymocytes in the absence of competitive precursor replenishment. J Exp Med 209:1397–1400
Cavazzana-Calvo M et al (2000) Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease. Science 288:669–672
De Ravin SS et al (2016) Lentiviral hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiency. Sci Transl Med 8:335ra357
Frey JR, Ernst B, Surh CD, Sprent J (1992) Thymus-grafted SCID mice show transient thymopoiesis and limited depletion of V beta 11 + T cells. J Exp Med 175:1067–1071
Gaspar HB et al (2004) Gene therapy of X-linked severe combined immunodeficiency by use of a pseudotyped gammaretroviral vector. Lancet 364:2181–2187
Gerby B et al (2014) SCL. LMO1 and Notch1 reprogram thymocytes into self-renewing cells. PLoS Genet 10(12):e1004768
Ginn SL et al (2010) Lymphomagenesis in SCID-X1 mice following lentivirus-mediated phenotype correction independent of insertional mutagenesis and gammac overexpression. Mol Ther 18:965–976
Ginn SL et al (2017) Limiting thymic precursor supply increases the risk of lymphoid malignancy in murine X-linked severe combined immunodeficiency. Mol Ther Nucleic Acids 6:1–14
Hacein-Bey-Abina S et al (2008) Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1. J Clin Investig 118:3132–3142
Hacein-Bey-Abina S et al (2014) A modified gamma-retrovirus vector for X-linked severe combined immunodeficiency N. Engl J Med 371:1407–1417
Howe SJ et al (2008) Insertional mutagenesis combined with acquired somatic mutations causes leukemogenesis following gene therapy of SCID-X1 patients. J Clin Investig 18:3143–3150
Martins VC et al (2012) Thymus-autonomous T cell development in the absence of progenitor import. J Exp Med 209:1409–1417
Martins VC et al (2014) Cell competition is a tumour suppressor mechanism in the thymus. Nature 509:465–470
McCormack MP et al (2010) The Lmo2 oncogene initiates leukemia in mice by inducing thymocyte self-renewal. Science 327:879–883
Peaudecerf L et al (2012) Thymocytes may persist and differentiate without any input from bone marrow progenitors. J Exp Med 209:1401–1408
Peaudecerf L, Krenn G, Goncalves P, Vasseur F, Rocha B (2016) Thymocytes self-renewal: a major hope or a major threat? Immunol Rev 271:173–184
Pike-Overzet K et al (2006) Gene therapy: is IL2RG oncogenic in T-cell development? Nature 443:E5–E7
Qasim W, Gaspar HB, Thrasher AJ (2014) “Darwinian” tumor-suppression model unsupported in clinical experience. Mol Ther 22:1562–1563
Ruggero K, Al-Assar O, Chambers JS, Codrington R, Brend T, Rabbitts TH (2016) LMO2 and IL2RG synergize in thymocytes to mimic the evolution of SCID-X1 gene therapy-associated T-cell leukaemia. Leukemia 30:1959–1962
Schiroli G et al (2017) Preclinical modeling highlights the therapeutic potential of hematopoietic stem cell gene editing for correction of SCID-X1. Sci Transl Med 9:eaan0820
Scobie L et al (2009) A novel model of SCID-X1 reconstitution reveals predisposition to retrovirus-induced lymphoma but no evidence of gammaC gene oncogenicity. Mol Ther 17:1031–1038
Shou Y, Ma Z, Lu T, Sorrentino BP (2006) Unique risk factors for insertional mutagenesis in a mouse model of XSCID gene therapy. Proc Natl Acad Sci USA 103:11730–11735
Takeda S, Rodewald HR, Arakawa H, Bluethmann H, Shimizu T (1996) MHC class II molecules are not required for survival of newly generated CD4 + T cells, but affect their long-term life span. Immunity 5:217–228
Tarantal AF et al (2012) Nonmyeloablative conditioning regimen to increase engraftment of gene-modified hematopoietic stem cells in young rhesus monkeys. Mol Ther 20:1033–1045. https://doi.org/10.1038/mt.2011.312
Thrasher AJ et al (2006) Gene therapy: X-SCID transgene leukaemogenicity. Nature 443:E5–E6
Woods NB, Bottero V, Schmidt M, von Kalle C, Verma IM (2006) Gene therapy: therapeutic gene causing lymphoma. Nature 440:1123
Acknowledgements
This work was supported by a Project Grant (632657) from the National Health & Medical Research Council (NHMRC) of Australia.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
SLG, MPM and IEA declare that they have no conflicts of interest.
Rights and permissions
About this article
Cite this article
Ginn, S.L., McCormack, M.P. & Alexander, I.E. Thymocyte self-renewal and oncogenic risk in immunodeficient mouse models: relevance for human gene therapy clinical trials targeting haematopoietic stem cell populations?. Mamm Genome 29, 771–776 (2018). https://doi.org/10.1007/s00335-018-9780-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00335-018-9780-5