Cell competition is a tumour suppressor mechanism in the thymus

Vera C. Martins, Katrin Busch, Dilafruz Juraeva, Carmen Blum, Carolin Ludwig, Volker Rasche, Felix Lasitschka, Sergey E. Mastitsky, Benedikt Brors, Thomas Hielscher, Hans Joerg Fehling and Hans-Reimer Rodewald ()
Additional contact information
Vera C. Martins: German Cancer Research Center, D-69120 Heidelberg, Germany
Katrin Busch: German Cancer Research Center, D-69120 Heidelberg, Germany
Dilafruz Juraeva: German Cancer Research Center, D-69120 Heidelberg, Germany
Carmen Blum: Institute of Immunology, University of Ulm, D-89081 Ulm, Germany
Carolin Ludwig: Institute of Immunology, University of Ulm, D-89081 Ulm, Germany
Volker Rasche: Core Facility Small Animal MRI, University of Ulm, D-89081 Ulm, Germany
Felix Lasitschka: Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany
Sergey E. Mastitsky: German Cancer Research Center, D-69120 Heidelberg, Germany
Benedikt Brors: German Cancer Research Center, D-69120 Heidelberg, Germany
Thomas Hielscher: German Cancer Research Center, D-69120 Heidelberg, Germany
Hans Joerg Fehling: Institute of Immunology, University of Ulm, D-89081 Ulm, Germany
Hans-Reimer Rodewald: German Cancer Research Center, D-69120 Heidelberg, Germany

Nature, 2014, vol. 509, issue 7501, 465-470

Abstract: 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.

Date: 2014
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DOI: 10.1038/nature13317

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