Notch signalling is a central regulator of differentiation in a variety of 
organisms and tissue types. Its activity is controlled by the multi-subunit 
γ-secretase (γSE) complex. 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 mutations. 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.