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

   

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, R. L.; Aifantis, I.
Article Title:	A novel tumour-suppressor function for the Notch pathway in myeloid leukaemia
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 Î 3-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. © 2011 Macmillan Publishers Limited. All rights reserved.
Keywords:	signal transduction; controlled study; protein expression; chronic myelomonocytic leukemia; mutation; leukemia, myelomonocytic, chronic; nonhuman; protein function; animal cell; mouse; animals; mice; animal tissue; cells, cultured; gene expression profiling; signaling; animal experiment; basic helix-loop-helix transcription factors; notch receptor; transcription factor hes 1; genetic transcription; cell differentiation; homeodomain proteins; tumor cells, cultured; enzyme activity; wild type; mice, inbred c57bl; cancer inhibition; gene expression regulation, neoplastic; receptors, notch; hematopoietic stem cells; hematopoiesis; hematopoietic stem cell; gene silencing; tumor; transcriptome; cell organelle; bioaccumulation; genes, tumor suppressor; notch1 receptor; hematology; notch2 receptor; notch3 receptor; granulocyte-macrophage progenitor cells; disease prevalence; granulocyte precursor
Journal Title:	Nature
Volume:	473
Issue:	7346
ISSN:	0028-0836
Publisher:	Nature Publishing Group
Date Published:	2011-05-12
Start Page:	230
End Page:	233
Language:	English
DOI:	10.1038/nature09999
PROVIDER:	scopus
PMCID:	PMC3093658
PUBMED:	21562564
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-79955915582&partnerID=40&md5=442d1405c9de48edf29bc4ef6d82362f
Notes:	--- - "Cited By (since 1996): 3" - "Export Date: 23 June 2011" - "CODEN: NATUA" - "Source: Scopus"

https://synapse.mskcc.org/synapse/works/has_related_data_chk/5767