Cell competition in the thymus

Cell competition is a tumour suppressor mechanism in the thymus.  Nature doi:10.1038/nature13317

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.

昨日、Natureのオンライン版で出てきた論文。マウスの胸腺では、骨髄由来の若いT-cell progenitorsが、胸腺の古いthymus-resident progenitorsをoutcompeteすることによってthymocyteのturnoverが起こっているというお話。そしてこのcell competitionによるturnoverが無くなると、補償的なself-renewalに依存し始めたthymus-resident progenitorsでは、gene expression profileに変化が起こってacute lymphoblastic leukaemiaに至るのである。

去年、マウスのearly embryoでendogenous cell competitionによってMyc発現レベルの高いものが選別されているという報告があったけど、今回はprogenitor cellsのturnoverがendogenousなnatural cell competitionによって起こっているという発見であり、さらにこのphysiological replacementがtumor suppressor mechanismとして機能しているというこのお話は、cell competitionという現象の意義を考えるにあたって非常に重要である、なんてことは言うまでもないか。

Cancer: Darwinian tumour suppression.  Nature doi:10.1038/nature13337

で、コチラはモレノ先輩による分かりやすい解説記事。しっかりと自身の「Fitness Fingerprints」説を宣伝しているあたり、先輩らしくてナイスですね。

「It is clear that exciting days lie ahead for the study of cell competition in relation to cancer.」確かに。