Abstract

Activating mutations in the Notch pathway promote tumorigenesis in T-cell leukaemias. Iannis Aifantis and colleagues now find that the same pathway suppresses the development of myeloid leukaemias. Inactivating the pathway in haematopoietic stem cells leads to myeloid disease resembling chronic myelomonocytic leukaemia (CMML), and mutations in Notch pathway genes can be found in patients with CMML. The Notch pathway is shown to suppress a myeloid differentiation program. These findings demonstrate that the Notch pathway exerts both oncogenic and tumour-suppressor functions in the haematopoietic system and regulates critical cell-fate decisions. 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.