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GPRC5C drives branched-chain amino acid metabolism in leukemogenesis

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 coh...

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Main Authors: Zhang, Yu Wei (Author) , Velasco-Hernandez, Talia (Author) , Mess, Julian (Author) , Lalioti, Maria-Eleni (Author) , Romero-Mulero, Mari Carmen (Author) , Obier, Nadine (Author) , Karantzelis, Nikolaos (Author) , Rettkowski, Jasmin (Author) , Schönberger, Katharina (Author) , Karabacz, Noémie (Author) , Jäcklein, Karin (Author) , Morishima, Tatsuya (Author) , Trincado, Juan Luis (Author) , Romecin, Paola (Author) , Martinez, Alba (Author) , Takizawa, Hitoshi (Author) , Shoumariyeh, Khalid (Author) , Renders, Simon (Author) , Zeiser, Robert (Author) , Pahl, Heike L. (Author) , Béliveau, François (Author) , Hébert, Josée (Author) , Lehnertz, Bernhard (Author) , Sauvageau, Guy (Author) , Menendez, Pablo (Author) , Cabezas Wallscheid, Nina (Author)
Format: Article (Journal)
Language:English
Published: December 26 2023
In: Blood advances
Year: 2023, Volume: 7, Issue: 24, Pages: 7525-7538
ISSN:2473-9537
DOI:10.1182/bloodadvances.2023010460
Subjects:
G-Protein gekoppelter Rezeptor
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1182/bloodadvances.2023010460
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Author Notes:Yu Wei Zhang, Talia Velasco-Hernandez, Julian Mess, Maria-Eleni Lalioti, Mari Carmen Romero-Mulero, Nadine Obier, Nikolaos Karantzelis, Jasmin Rettkowski, Katharina Schönberger, Noémie Karabacz, Karin Jäcklein, Tatsuya Morishima, Juan Luis Trincado, Paola Romecin, Alba Martinez, Hitoshi Takizawa, Khalid Shoumariyeh, Simon Renders, Robert Zeiser, Heike L. Pahl, François Béliveau, Josée Hébert, Bernhard Lehnertz, Guy Sauvageau, Pablo Menendez, and Nina Cabezas-Wallscheid
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Summary: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.
Item Description:Gesehen am 12.12.2024
Physical Description:Online Resource
ISSN:2473-9537
DOI:10.1182/bloodadvances.2023010460

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