Abstract

Cell competition is an emerging principle underlying selection for cellular fitness during development and disease. Competition may be relevant for cancer, but an experimental link between defects in competition and tumorigenesis is elusive. In the thymus, T lymphocytes develop from precursors that are constantly replaced by bone-marrow-derived progenitors. Here we show that in mice this turnover is regulated by natural cell competition between ‘young’ bone-marrow-derived and ‘old’ thymus-resident progenitors that, although genetically identical, execute differential gene expression programs. Disruption of cell competition leads to progenitor self-renewal, upregulation of Hmga1, transformation, and T-cell acute lymphoblastic leukaemia (T-ALL) resembling the human disease in pathology, genomic lesions, leukaemia-associated transcripts, and activating mutations in Notch1. Hence, cell competition is a tumour suppressor mechanism in the thymus. Failure to select fit progenitors through cell competition may explain leukaemia in X-linked severe combined immune deficiency patients who showed thymus-autonomous T-cell development after therapy with gene-corrected autologous progenitors.

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Gene Expression Omnibus

Data deposits

Microarray data analysed and reported here have been deposited in the NCBI Gene Expression Omnibus40 and are accessible through GEO accession number GSE56419.

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Acknowledgements

We thank A. Tietz and T. Arnsperger for technical assistance, T. Ashworth and J. Aster, M. Nussenzweig and P. Fink for materials and mice, the animal facilities for mouse husbandry, S. Henze, O. Heil and E. Korpelainen for expression array experiments and support on Chipster. We thank B. Edgar, L. Johnston, T. Boehm, A. Rudensky, R. Medzhitov, M. Muckenthaler, A. Kulodzik, T. Sanda, T. Look, P. Lichter, T. Feyerabend and I. Rode for help and discussions. H.-R.R. was supported by ERC Advanced Grant No. 233074, DFG-SFB 938-project L, and the Helmholtz PCCC Alliance.

Author information

Affiliations

  1. Division of Cellular Immunology, German Cancer Research Center, D-69120 Heidelberg, Germany

    • Vera C. Martins
    • , Katrin Busch
    •  & Hans-Reimer Rodewald
  2. Institute of Immunology, University of Ulm, D-89081 Ulm, Germany

    • Vera C. Martins
    • , Carmen Blum
    • , Carolin Ludwig
    •  & Hans Joerg Fehling
  3. Division of Theoretical Bioinformatics, German Cancer Research Center, D-69120 Heidelberg, Germany

    • Dilafruz Juraeva
    • , Sergey E. Mastitsky
    •  & Benedikt Brors
  4. Core Facility Small Animal MRI, University of Ulm, D-89081 Ulm, Germany

    • Volker Rasche
  5. Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany

    • Felix Lasitschka
  6. Division of Biostatistics, German Cancer Research Center, D-69120 Heidelberg, Germany

    • Thomas Hielscher

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Contributions

V.C.M. designed and performed experiments, and wrote the paper; K.B., C.B. and C.L. performed experiments; V.C.M., D.J., S.E.M., B.B. and T.H. performed bioinformatic analyses; V.R. obtained the magnetic resonance imaging images; F.L. evaluated the pathological findings; H.J.F. provided essential support and edited the paper; and H.-R.R. conceived and supervised the study, and wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Hans-Reimer Rodewald.

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    Supplementary Information

    This file contains contains Supplementary Discussion, Supplementary References, and Supplementary Tables 1–5. Supplementary Tables 1 and 2 refer to genomic gains and losses detected in T-ALL by array comparative genomic hybridization (aCGH), considered cancer-related according to the Ingenuity Pathway Analysis. Supplementary Tables 3–5 refer to ≥2 fold-change differences in transcriptome analyses between normal thymus versus thymus grafts (Table 3), between thymus grafts versus T-ALL (Table 4), and between normal thymus versus T-ALL (Table 5). Genes displayed were considered to be cancer-related according to Ingenuity Pathway Analysis.

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https://doi.org/10.1038/nature13317

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