Notch signalling is a central regulator of differentiation in a variety of organisms and tissue types(1). Its activity is controlled by the multisubunit gamma-secretase (gamma SE) complex(2). 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(3). 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.
A novel tumour-suppressor function for the Notch pathway in myeloid leukaemia / Klinakis, A; Lobry, C; Abdel-Wahab, O; Oh, P; Haeno, H; Buonamici, S; van De Walle, I; Cathelin, S; Trimarchi, T; Araldi, E; Liu, C; Ibrahim, S; Beran, M; Zavadil, J; Efstratiadis, A; Taghon, T; Michor, F; Levine, Rl; Aifantis, I. - In: NATURE. - ISSN 0028-0836. - 473:7346(2011), pp. 230-+. [10.1038/nature09999]
A novel tumour-suppressor function for the Notch pathway in myeloid leukaemia
Araldi E;
2011-01-01
Abstract
Notch signalling is a central regulator of differentiation in a variety of organisms and tissue types(1). Its activity is controlled by the multisubunit gamma-secretase (gamma SE) complex(2). 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(3). 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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
