白血病干细胞（LSCs）与健康的造血干细胞（HSCs）共享许多特征。G蛋白偶联受体家族C群5成员C（GPRC5C）是HSC休眠的调节因子。然而，GPRC5C在急性髓系白血病（AML）中的功能尚待确定。在患者AML队列内，高GPRC5C水平与更差的生存率相关。异位Gprc5c表达通过激活NF-κB增加AML的侵袭性，这导致细胞内支链氨基酸（BCAAs）水平增加，代谢状态改变。失去Gprc5c后，这种致癌代谢谱被逆转，同时抑制了白血病发生能力。使用JPH203靶向BCAA转运蛋白SLC7A5可以抑制氧化磷酸化并在老鼠和患者AML样本中产生强烈的抗白血病效果，同时保护健康的骨髓（BM）细胞。在Venetoclax和Azacitidine存在的情况下，这种抗白血病效应得到了加强。我们的结果表明，在AML中，GPRC5C-NF-κB-SLC7A5-BCAAs轴是一个治疗靶点，可以损害白血病干细胞的功能。版权所有© 2023美国血液学会。

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.Copyright © 2023 American Society of Hematology.