NOTCH is a key regulator of human T-cell acute leukemia initiating cell activity.
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.
Armstrong
Florence
F
Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique, Unite Mixte de Recherche 8104 Paris, France.
Brunet de la Grange
Philippe
P
Gerby
Bastien
B
Rouyez
Marie-Christine
MC
Calvo
Julien
J
Fontenay
Michaéla
M
Boissel
Nicolas
N
Dombret
Hervé
H
Baruchel
André
A
Landman-Parker
Judith
J
Roméo
Paul-Henri
PH
Ballerini
Paola
P
Pflumio
Françoise
F
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
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