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 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.
authors.affiliation: Biomedical Research Foundation, Academy of Athens, Athens, Greece.
authors.forename: Apostolos
authors.initials: A
authors.lastname: Klinakis
authors.forename: Camille
authors.initials: C
authors.lastname: Lobry
authors.forename: Omar
authors.initials: O
authors.lastname: Abdel-Wahab
authors.forename: Philmo
authors.initials: P
authors.lastname: Oh
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Haeno
authors.forename: Silvia
authors.initials: S
authors.lastname: Buonamici
authors.forename: Inge
authors.initials: I
authors.lastname: van De Walle
authors.forename: Severine
authors.initials: S
authors.lastname: Cathelin
authors.forename: Thomas
authors.initials: T
authors.lastname: Trimarchi
authors.forename: Elisa
authors.initials: E
authors.lastname: Araldi
authors.forename: Cynthia
authors.initials: C
authors.lastname: Liu
authors.forename: Sherif
authors.initials: S
authors.lastname: Ibrahim
authors.forename: Miroslav
authors.initials: M
authors.lastname: Beran
authors.forename: Jiri
authors.initials: J
authors.lastname: Zavadil
authors.forename: Argiris
authors.initials: A
authors.lastname: Efstratiadis
authors.forename: Tom
authors.initials: T
authors.lastname: Taghon
authors.forename: Franziska
authors.initials: F
authors.lastname: Michor
authors.forename: Ross L
authors.initials: RL
authors.lastname: Levine
authors.forename: Iannis
authors.initials: I
authors.lastname: Aifantis
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D055014:Granulocyte-Macrophage Progenitor Cells / Q000166:cytology / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D015477:Leukemia, Myelomonocytic, Chronic / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D051880:Receptors, Notch / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D000072056:Transcription Factor HES-1; D014407:Tumor Cells, Cultured
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D051880:Receptors, Notch; D000072056:Transcription Factor HES-1; C489734:Hes1 protein, mouse