A novel tumour-suppressor function for the Notch pathway in myeloid leukaemia
A partir de l'analyse d'échantillons prélevés sur 42 patients atteints d'une leucémie myélomonocytaire chronique, cette étude suggère que la voie de signalisation Notch peut jouer un rôle de suppresseur ou de promoteur de tumeurs au sein d'un même tissu
Notch signalling is a central regulator of differentiation in a variety of organisms and tissue types1. Its activity is controlled by the multi-subunit
γ-secretase (γSE) complex2. Although Notch signalling can play both oncogenic and tumour-suppressor roles in solid tumours, in the haematopoietic system it is exclusively oncogenic, notably in T-cell acute lymphoblastic leukaemia, a disease characterized by Notch1-activating mutations3. Here we identify novel somatic-inactivating Notch pathway mutations in a fraction of patients with chronic myelomonocytic leukaemia (CMML). Inactivation of Notch signalling in mouse haematopoietic stem cells (HSCs) results in an aberrant accumulation of granulocyte/monocyte progenitors (GMPs), extramedullary haematopoieisis and the induction of CMML-like disease. Transcriptome analysis revealed that Notch signalling regulates an extensive myelomonocytic-specific gene signature, through the direct suppression of gene transcription by the Notch target Hes1. Our studies identify a novel role for Notch signalling during early haematopoietic stem cell differentiation and suggest that the Notch pathway can play both tumour-promoting and -suppressive roles within the same tissue.
Nature , résumé, 2010