A novel tumour-suppressor function for the Notch pathway in myeloid leukaemia Academic Article uri icon

Overview

MeSH Major

  • Gene Expression Regulation, Neoplastic
  • Genes, Tumor Suppressor
  • Leukemia, Myelomonocytic, Chronic
  • Receptors, Notch
  • Signal Transduction

abstract

  • 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.

publication date

  • May 12, 2011

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3093658

Digital Object Identifier (DOI)

  • 10.1038/nature09999

PubMed ID

  • 21562564

Additional Document Info

start page

  • 230

end page

  • 3

volume

  • 473

number

  • 7346