title: NOTCH is a key regulator of human T-cell acute leukemia initiating cell activity.
abstract: Understanding the pathways that regulate the human T-cell acute lymphoblastic leukemia (T-ALL) initiating cells (T-LiC) activity has been hampered by the lack of biologic assays in which this human disease can be studied. Here we show that coculture of primary human T-ALL with a mouse stromal cell line expressing the NOTCH ligand delta-like-1 (DL1) reproducibly allowed maintenance of T-LiC and long-term growth of blast cells. Human T-ALL mutated or not on the NOTCH receptor required sustained activation of the NOTCH pathway via receptor/ligand interaction for growth and T-LiC activity. On the reverse, inhibition of the NOTCH pathway during primary cultures abolished in vitro cell growth and in vivo T-LiC activity. Altogether, these results demonstrate the major role of the NOTCH pathway activation in human T-ALL development and in the maintenance of leukemia-initiating cells.
authors.affiliation: Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique, Unite Mixte de Recherche 8104 Paris, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Armstrong
authors.forename: Philippe
authors.initials: P
authors.lastname: Brunet de la Grange
authors.forename: Bastien
authors.initials: B
authors.lastname: Gerby
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Rouyez
authors.forename: Julien
authors.initials: J
authors.lastname: Calvo
authors.forename: Michaéla
authors.initials: M
authors.lastname: Fontenay
authors.forename: Nicolas
authors.initials: N
authors.lastname: Boissel
authors.forename: Hervé
authors.initials: H
authors.lastname: Dombret
authors.forename: André
authors.initials: A
authors.lastname: Baruchel
authors.forename: Judith
authors.initials: J
authors.lastname: Landman-Parker
authors.forename: Paul-Henri
authors.initials: PH
authors.lastname: Roméo
authors.forename: Paola
authors.initials: P
authors.lastname: Ballerini
authors.forename: Françoise
authors.initials: F
authors.lastname: Pflumio
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D000818:Animals; D002135:Calcium-Binding Proteins; D002450:Cell Communication / Q000502:physiology; D018929:Cell Culture Techniques / Q000379:methods; D018920:Coculture Techniques; D019675:Genes, T-Cell Receptor gamma / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009842:Oligopeptides / Q000494:pharmacology; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D017154:Stromal Cells / Q000166:cytology / Q000502:physiology; D014407:Tumor Cells, Cultured
chemical_list: D002135:Calcium-Binding Proteins; C512941:DLK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C497761:NOTCH1 protein, human; D009842:Oligopeptides; D051881:Receptor, Notch1; C523462:benzyloxycarbonyl-leucyl-leucyl-norleucinal; D053829:Amyloid Precursor Protein Secretases