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A novel tumour-suppressor function for the Notch pathway in myeloid leukaemia.

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.

Pubmed ID: 21562564

Authors

  • 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

Journal

Nature

Publication Data

May 12, 2011

Associated Grants

  • Agency: NCI NIH HHS, Id: 1P01CA97403
  • Agency: NCI NIH HHS, Id: R01 CA105129
  • Agency: NCI NIH HHS, Id: R01 CA105129-07
  • Agency: NCI NIH HHS, Id: R01 CA133379
  • Agency: NCI NIH HHS, Id: R01 CA133379-04
  • Agency: NCI NIH HHS, Id: R01 CA149655
  • Agency: NCI NIH HHS, Id: R01 CA149655-03
  • Agency: NCI NIH HHS, Id: R01CA105129
  • Agency: NCI NIH HHS, Id: R01CA1328234
  • Agency: NCI NIH HHS, Id: R01CA133379
  • Agency: NCI NIH HHS, Id: R01CA149655
  • Agency: NCI NIH HHS, Id: R21 CA141399
  • Agency: NCI NIH HHS, Id: R21 CA141399-02
  • Agency: NCI NIH HHS, Id: R21CA141399
  • Agency: NIGMS NIH HHS, Id: T32 GM007308
  • Agency: NCI NIH HHS, Id: U54CA143798
  • Agency: Howard Hughes Medical Institute, Id:
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors
  • Cell Differentiation
  • Cells, Cultured
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Gene Silencing
  • Genes, Tumor Suppressor
  • Granulocyte-Macrophage Progenitor Cells
  • Hematopoietic Stem Cells
  • Homeodomain Proteins
  • Humans
  • Leukemia, Myelomonocytic, Chronic
  • Mice
  • Mice, Inbred C57BL
  • Mutation
  • Receptors, Notch
  • Signal Transduction
  • Tumor Cells, Cultured