Submitted February 12, 2008
Accepted September 16, 2008
NOTCH is a key regulator of human T-cell acute leukaemia initiating cell activity
Florence Armstrong, Philippe Brunet de la Grange, Bastien Gerby, Marie-Christine Rouyez, Julien Calvo, Michaela Fontenay, Nicolas Boissel, Herve Dombret, Andre Baruchel, Judith Landman-Parker, Paul-Henri Romeo, Paola Ballerini, and Francoise Pflumio*
Institut Cochin, Universite Paris Descartes, CNRS (UMR 8104), Paris, France
Inserm, U567, Paris, France
Service d'Hematologie et d'Oncologie Pediatrique et Adulte, Hopital Saint-Louis, AP-HP, Paris, France
Laboratoire d'hematologie, Sevice d'hematologie et d'oncologie pediatrique, Hopital Trousseau, Paris, France
Laboratoire des cellules souches hematopoietiques et leucemiques, Institut de radiobiologie cellulaire et moleculaire, Paris, France
* Corresponding author; email: francoise.pflumio{at}cea.fr.
Understanding the pathways that regulate the human T-cell acute leukaemia (T-ALL) initiating cells (T-LiC) activity has been hampered by the lack of biological assays in which this human disease can be studied. Here we show that co-culture of primary human T-ALL with a mouse stromal cell line expressing the NOTCH ligand delta-like-1 (DL1) reproducibly allowed maintenance of T-ALL leukaemia-initiating cells (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 and 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 leukaemia-initiating cells.
