Cell competition is a tumour suppressor mechanism in the thymus.
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.
1] Division of Cellular Immunology, German Cancer Research Center, D-69120 Heidelberg, Germany [2] Institute of Immunology, University of Ulm, D-89081 Ulm, Germany.
Vera C
VC
Martins
Division of Cellular Immunology, German Cancer Research Center, D-69120 Heidelberg, Germany.
Katrin
K
Busch
Division of Theoretical Bioinformatics, German Cancer Research Center, D-69120 Heidelberg, Germany.
Dilafruz
D
Juraeva
Institute of Immunology, University of Ulm, D-89081 Ulm, Germany.
Carmen
C
Blum
Institute of Immunology, University of Ulm, D-89081 Ulm, Germany.
Carolin
C
Ludwig
Core Facility Small Animal MRI, University of Ulm, D-89081 Ulm, Germany.
Volker
V
Rasche
Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany.
Felix
F
Lasitschka
Division of Theoretical Bioinformatics, German Cancer Research Center, D-69120 Heidelberg, Germany.
Sergey E
SE
Mastitsky
Division of Theoretical Bioinformatics, German Cancer Research Center, D-69120 Heidelberg, Germany.
Benedikt
B
Brors
Division of Biostatistics, German Cancer Research Center, D-69120 Heidelberg, Germany.
Thomas
T
Hielscher
Institute of Immunology, University of Ulm, D-89081 Ulm, Germany.
Hans Joerg
HJ
Fehling
Division of Cellular Immunology, German Cancer Research Center, D-69120 Heidelberg, Germany.
Hans-Reimer
HR
Rodewald
D000818:Animals; D002455:Cell Division; D002465:Cell Movement; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D024003:HMGA Proteins / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000473:pathology*; D051881:Receptor, Notch1 / Q000235:genetics; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D013950:Thymus Gland / Q000166:cytology* / Q000473:pathology; D059467:Transcriptome / Q000235:genetics
D024003:HMGA Proteins; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1