Publication Date:
2011-05-13
Description:
Notch signalling is a central regulator of differentiation in a variety of organisms and tissue types. Its activity is controlled by the multi-subunit gamma-secretase (gammaSE) 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3093658/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3093658/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Klinakis, Apostolos -- Lobry, Camille -- Abdel-Wahab, Omar -- Oh, Philmo -- Haeno, Hiroshi -- Buonamici, Silvia -- van De Walle, Inge -- Cathelin, Severine -- Trimarchi, Thomas -- Araldi, Elisa -- Liu, Cynthia -- Ibrahim, Sherif -- Beran, Miroslav -- Zavadil, Jiri -- Efstratiadis, Argiris -- Taghon, Tom -- Michor, Franziska -- Levine, Ross L -- Aifantis, Iannis -- 1P01CA97403/CA/NCI NIH HHS/ -- R01 CA105129/CA/NCI NIH HHS/ -- R01 CA105129-07/CA/NCI NIH HHS/ -- R01 CA133379/CA/NCI NIH HHS/ -- R01 CA133379-04/CA/NCI NIH HHS/ -- R01 CA149655/CA/NCI NIH HHS/ -- R01 CA149655-03/CA/NCI NIH HHS/ -- R01CA105129/CA/NCI NIH HHS/ -- R01CA1328234/CA/NCI NIH HHS/ -- R01CA133379/CA/NCI NIH HHS/ -- R01CA149655/CA/NCI NIH HHS/ -- R21 CA141399/CA/NCI NIH HHS/ -- R21 CA141399-02/CA/NCI NIH HHS/ -- R21CA141399/CA/NCI NIH HHS/ -- U54CA143798/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 May 12;473(7346):230-3. doi: 10.1038/nature09999.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Biomedical Research Foundation, Academy of Athens, Athens, Greece.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21562564" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Basic Helix-Loop-Helix Transcription Factors/metabolism
;
Cell Differentiation
;
Cells, Cultured
;
Gene Expression Profiling
;
*Gene Expression Regulation, Neoplastic
;
Gene Silencing
;
Genes, Tumor Suppressor/*physiology
;
Granulocyte-Macrophage Progenitor Cells/cytology/metabolism
;
Hematopoietic Stem Cells/cytology/metabolism
;
Homeodomain Proteins/metabolism
;
Humans
;
Leukemia, Myelomonocytic, Chronic/*genetics/*pathology
;
Mice
;
Mice, Inbred C57BL
;
Mutation
;
Receptors, Notch/deficiency/*genetics/*metabolism
;
*Signal Transduction
;
Tumor Cells, Cultured
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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