GPRC5C Drives Branched-Chain Amino Acid Metabolism in Leukemogenesis.
Yu Wei ZhangTalía Velasco-HernandezJulian MessMaria-Eleni LaliotiMari Carmen Romero-MuleroNadine ObierNikolaos KarantzelisJasmin RettkowskiKatharina SchönbergerNoémie KarabaczKarin JäckleinTatsuya MorishimaJuan Luis TrincadoPaola RomecinAlba Martinez-MorenoHitoshi TakizawaKhalid ShoumariyehSimon RendersRobert ZeiserHeike Luise PahlFrançois BéliveauJosée HébertBernhard LehnertzGuy SauvageauPablo MenendezNina Cabezas-WallscheidPublished in: Blood advances (2023)
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 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 anti-leukemia effects, specifically in mouse and patient AML samples while sparing healthy bone marrow (BM) cells. This anti-leukemia 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.
Keyphrases
- acute myeloid leukemia
- bone marrow
- stem cells
- amino acid
- allogeneic hematopoietic stem cell transplantation
- signaling pathway
- induced apoptosis
- oxidative stress
- case report
- mesenchymal stem cells
- lps induced
- poor prognosis
- pi k akt
- nuclear factor
- inflammatory response
- transcription factor
- risk assessment
- immune response
- cell therapy
- robot assisted
- reactive oxygen species
- cell death
- cell cycle arrest
- toll like receptor
- binding protein