GPRC5C drives branched-chain amino acid metabolism in leukemogenesis
Zhang, Yu Wei (Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany)
Velasco-Hernández, Talia (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Mess, Julian (University of Freiburg)
Lalioti, Maria Eleni (Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany)
Romero-Mulero, Mari Carmen (University of Freiburg, Germany)
Obier, Nadine (Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany)
Karantzelis, Nikolaos (University Medical Center Freiburg, Germany)
Rettkowski, Jasmin (University of Freiburg, Germany)
Schönberger, Katharina (Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany)
Karabacz, Noemie (Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany)
Jäcklein, Karin (Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany)
Morishima, Tatsuya (Kumamoto University, Japan)
Trincado Alonso, Juan Luis, 1987- (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Romecin, Paola (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Martinez, Alba (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Takizawa, Hitoshi (Kumamoto University, Japan)
Shoumariyeh, Khalid (University of Freiburg, Germany)
Renders, Simon (Heidelberg University Hospital (Alemanya))
Zeiser, Robert (University of Freiburg, Germany)
Pahl, Heike L. (University Medical Center Freiburg, Germany)
Béliveau, François (Quebec leukemia cell bank. Hopital Maisonneuve-Rosemont, Montreal, Canada)
Hébert, Josee (Quebec leukemia cell bank. Hopital Maisonneuve-Rosemont, Montreal, Canada)
Lehnertz, Bernhard (University of Montreal, Canada)
Sauvageau, Guy (University of Montreal, Canada)
Menendez, Pablo (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Cabezas-Wallscheid, Nina (Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany)

Fecha:	2023
Resumen:	Leukemia stem cells (LSCs) share numerous features with healthy hematopoietic stem cells (HSCs). G-protein coupled receptor family C group 5 member C (GPRC5C) is a regulator of HSC dormancy. However, GPRC5C functionality in acute myeloid leukemia (AML) is yet to be determined. Within patient AML cohorts, high GPRC5C levels correlated with poorer survival. Ectopic Gprc5c expression increased AML aggression through the activation of NF-κB, which resulted in an altered metabolic state with increased levels of intracellular branched-chain amino acids (BCAAs). This onco-metabolic profile was reversed upon loss of Gprc5c, which also abrogated the leukemia-initiating potential. Targeting the BCAA transporter SLC7A5 with JPH203 inhibited oxidative phosphorylation and elicited strong antileukemia effects, specifically in mouse and patient AML samples while sparing healthy bone marrow cells. This antileukemia effect was strengthened in the presence of venetoclax and azacitidine. Our results indicate that the GPRC5C-NF-κB-SLC7A5-BCAAs axis is a therapeutic target that can compromise leukemia stem cell function in AML.
Ayudas:	European Commission. Horizon 2020 759206 European Commission. Horizon 2020 813091
Nota:	Altres ajuts: Jose Carreras Leukämie-Stiftung
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Publicado en:	Blood advances, Vol. 7 Núm. 24 (december 2023) , p. 7525-7538, ISSN 2473-9537

DOI: 10.1182/bloodadvances.2023010460
PMID: 37639313

14 p, 2.7 MB

El registro aparece en las colecciones:
Documentos de investigación > Documentos de los grupos de investigación de la UAB > Centros y grupos de investigación (producción científica) > Ciencias de la salud y biociencias > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP) > Instituto de Investigación contra la Leucemia Josep Carreras
Artículos > Artículos de investigación
Artículos > Artículos publicados