GPRC5C drives branched-chain amino acid metabolism in leukemogenesis-Reference-Cited by-同舟云学术

GPRC5C drives branched-chain amino acid metabolism in leukemogenesis

Published:2023-12-15 Issue:24 Volume:7 Page:7525-7538
ISSN:2473-9529
Container-title:Blood Advances
language:en
Short-container-title:

Author:

Zhang Yu Wei¹,Velasco-Hernandez Talia²^ORCID,Mess Julian¹³⁴⁵,Lalioti Maria-Eleni¹,Romero-Mulero Mari Carmen¹³^ORCID,Obier Nadine¹,Karantzelis Nikolaos⁶,Rettkowski Jasmin¹³⁴⁵,Schönberger Katharina¹,Karabacz Noémie¹,Jäcklein Karin¹,Morishima Tatsuya⁷⁸^ORCID,Trincado Juan Luis²,Romecin Paola²,Martinez Alba²,Takizawa Hitoshi⁷⁸^ORCID,Shoumariyeh Khalid⁹¹⁰,Renders Simon¹¹,Zeiser Robert⁹,Pahl Heike L.⁶^ORCID,Béliveau François¹²,Hébert Josée¹²¹³¹⁴,Lehnertz Bernhard¹⁵,Sauvageau Guy¹⁵,Menendez Pablo²¹⁶¹⁷¹⁸,Cabezas-Wallscheid Nina¹⁵

Affiliation:

1. 1Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany

2. 2Department of Biomedicine, Josep Carreras Leukaemia Research Institute, School of Medicine, University of Barcelona, Barcelona, Spain

3. 3Faculty of Biology, University of Freiburg, Freiburg, Germany

4. 4Spemann Graduate School for Biology and Medicine, University of Freiburg, Freiburg, Germany

5. 5Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany

6. 6Department of Hematology, Oncology and Stem Cell Transplantation, University Medical Center Freiburg, Freiburg, Germany

7. 7Laboratory of Stem Cell Stress, International Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan

8. 8Laboratory of Hematopoietic Stem Cell Engineering, International Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan

9. 9Department of Medicine I, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany

10. 10German Cancer Consortium, Partner Site Freiburg, and German Cancer Research Center, Heidelberg, Germany

11. 11Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany

12. 16Quebec leukemia cell bank, Hôpital Maisonneuve-Rosemont, Montréal, QC, Canada

13. 17Division of Hematology and Oncology, Hôpital Maisonneuve-Rosemont, Montréal, QC, Canada

14. 18Department of Medicine, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada

15. 12Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Canada

16. 13Centro de Investigación Biomédica en Red de Cáncer, ISIII, Barcelona, Spain

17. 14RICORS-TERAV Network, ISCIII, Madrid, Spain

18. 15Instituciò Catalana de Recerca i Estudis Avançats, Barcelona, Spain

Abstract

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.

Publisher

American Society of Hematology

Subject

Hematology

Link

https://ashpublications.org/bloodadvances/article-pdf/7/24/7525/2177929/blooda_adv-2023-010460-main.pdf

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