RT Journal Article
T1 Downregulation of Glutamine Synthetase, not glutaminolysis, is responsible for glutamine addiction in Notch1-driven acute lymphoblastic leukemia
A1 Nguyen, Tra Ly
A1 Nokin, Marie-Julie
A1 Terés, Silvia
A1 Tomé, Mercedes
A1 Bodineau, Clément
A1 Galmar, Oriane
A1 Pasquet, Jean-Max
A1 Rousseau, Benoit
A1 van Liempd, Sebastian
A1 Falcon-Perez, Juan Manuel
A1 Richard, Elodie
A1 Muzotte, Elodie
A1 Rezvani, Hamid-Reza
A1 Priault, Muriel
A1 Bouchecareilh, Marion
A1 Redonnet-Vernhet, Isabelle
A1 Calvo, Julien
A1 Uzan, Benjamin
A1 Pflumio, Françoise
A1 Fuentes, Patricia
A1 Toribio, Maria L.
A1 Khatib, Abdel-Majid
A1 Soubeyran, Pierre
A1 Murdoch, Piedad del Socorro
A1 Durán, Raúl V.
K1 Glutamine
K1 Glutamine synthetase
K1 Metabolic addiction
K1 mTORC1
K1 Notch1
K1 T-cell acute lymphoblastic leukemia
K1 Downregulation
K1 Cell line
K1 Glutamina
K1 Glutamato-amoníaco ligasa
K1 Metabolismo
K1 Diana mecanicista del complejo 1 de la rapamicina
K1 Receptor Notch1
K1 Leucemia-linfoma linfoblástico de células T precursoras
K1 Regulación hacia abajo
K1 Línea celular
AB The cellular receptor Notch1 is a central regulator of T-cell development, and as a consequence, Notch1 pathway appears upregulated in > 65% of the cases of T-cell acute lymphoblastic leukemia (T-ALL). However, strategies targeting Notch1 signaling render only modest results in the clinic due to treatment resistance and severe side effects. While many investigations reported the different aspects of tumor cell growth and leukemia progression controlled by Notch1, less is known regarding the modifications of cellular metabolism induced by Notch1 upregulation in T-ALL. Previously, glutaminolysis inhibition has been proposed to synergize with anti-Notch therapies in T-ALL models. In this work, we report that Notch1 upregulation in T-ALL induced a change in the metabolism of the important amino acid glutamine, preventing glutamine synthesis through the downregulation of glutamine synthetase (GS). Downregulation of GS was responsible for glutamine addiction in Notch1-driven T-ALL both in vitro and in vivo. Our results also confirmed an increase in glutaminolysis mediated by Notch1. Increased glutaminolysis resulted in the activation of the mammalian target of rapamycin complex 1 (mTORC1) pathway, a central controller of cell growth. However, glutaminolysis did not play any role in Notch1-induced glutamine addiction. Finally, the combined treatment targeting mTORC1 and limiting glutamine availability had a synergistic effect to induce apoptosis and to prevent Notch1-driven leukemia progression. Our results placed glutamine limitation and mTORC1 inhibition as a potential therapy against Notch1-driven leukemia.
PB Wiley
SN 1574-7891
YR 2020
FD 2020-12-12
LK http://hdl.handle.net/10668/4584
UL http://hdl.handle.net/10668/4584
LA en
NO Nguyen TL, Nokin MJ, Terés S, Tomé M, Bodineau C, Galmar O, et al. Downregulation of Glutamine Synthetase, not glutaminolysis, is responsible for glutamine addiction in Notch1-driven acute lymphoblastic leukemia. Mol Oncol. 2021 May;15(5):1412-1431
DS RISalud
RD Apr 11, 2025