Thymocyte self-renewal and oncogenic risk in immunodeficient mouse models: relevance for human gene therapy clinical trials targeting haematopoietic stem cell populations?

Mamm Genome. 2018 Dec;29(11-12):771-776. doi: 10.1007/s00335-018-9780-5. Epub 2018 Sep 4.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Adaptor Proteins, Signal Transducing / immunology
  • Animals
  • Carcinogenesis / genetics*
  • Carcinogenesis / immunology
  • Cell Self Renewal / immunology
  • Cell Transformation, Neoplastic / immunology
  • Disease Models, Animal
  • Genetic Therapy
  • Hematopoietic Stem Cells / immunology
  • Humans
  • LIM Domain Proteins / genetics*
  • LIM Domain Proteins / immunology
  • Mice
  • Neoplasms / genetics
  • Neoplasms / immunology*
  • Neoplastic Stem Cells / immunology
  • Thymocytes / immunology*

Substances

  • Adaptor Proteins, Signal Transducing
  • LIM Domain Proteins
  • Lmo2 protein, mouse