GPRC5C drives branched-chain amino acid metabolism in leukemogenesis

Abstract: 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

Standort
Deutsche Nationalbibliothek Frankfurt am Main
Umfang
Online-Ressource
Sprache
Englisch
Anmerkungen
Blood advances. - 7, 24 (2023) , 7525-7538, ISSN: 2473-9537

Klassifikation
Medizin, Gesundheit

Ereignis
Veröffentlichung
(wo)
Freiburg
(wer)
Universität
(wann)
2023
Urheber
Zhang, Yu Wei
Mess, Julian
Lalioti, Maria-Eleni
Romero-Mulero, Mari Carmen
Obier, Nadine
Karantzelis, Nikolaos
Rettkowski, Jasmin
Schönberger, Katharina
Karabacz, Noémie
Jäcklein, Karin
Shoumariyeh, Khalid
Zeiser, Robert
Pahl, Heike L.
Cabezas Wallscheid, Nina

DOI
10.1182/bloodadvances.2023010460
URN
urn:nbn:de:bsz:25-freidok-2389621
Rechteinformation
Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
Letzte Aktualisierung
15.08.2025, 07:39 MESZ

Datenpartner

Dieses Objekt wird bereitgestellt von:
Deutsche Nationalbibliothek. Bei Fragen zum Objekt wenden Sie sich bitte an den Datenpartner.

Beteiligte

Entstanden

  • 2023

Ähnliche Objekte (12)