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

Nature | May 12, 2011

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 RIS Download

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 | Transcription Factor HES-1 | Tumor Cells, Cultured

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Associated grants

  • Agency: NCI NIH HHS, Id: 1P01CA97403
  • Agency: NCI NIH HHS, Id: U54 CA143798
  • Agency: NCI NIH HHS, Id: P01 CA097403
  • Agency: NCI NIH HHS, Id: R01 CA133379
  • Agency: NCI NIH HHS, Id: R01CA133379
  • Agency: NCI NIH HHS, Id: R21CA141399
  • Agency: NCI NIH HHS, Id: R01 CA149655
  • Agency: NCI NIH HHS, Id: R01 CA105129
  • Agency: NCI NIH HHS, Id: R01 CA133379-04
  • Agency: NCI NIH HHS, Id: R01CA1328234
  • Agency: NCI NIH HHS, Id: R21 CA141399-02
  • Agency: Howard Hughes Medical Institute, Id: R21 CA141399
  • Agency: NCI NIH HHS, Id: R01CA149655
  • Agency: NCI NIH HHS, Id: R01 CA105129-07
  • Agency: NCI NIH HHS, Id: U54CA143798
  • Agency: NCI NIH HHS, Id: R01CA105129
  • Agency: NCI NIH HHS, Id: R01 CA149655-03
  • Agency: NCI NIH HHS, Id:

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