Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
Department of Biomedicine, Josep Carreras Leukaemia Research Institute, School of Medicine, University of Barcelona, Barcelona, Spain.
Blood Adv. 2023 Dec 26;7(24):7525-7538. doi: 10.1182/bloodadvances.2023010460.
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.
白血病干细胞 (LSCs) 与健康造血干细胞 (HSCs) 具有许多共同特征。G 蛋白偶联受体家族 C 组 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) 中的功能尚未确定。在患者 AML 队列中，GPRC5C 水平较高与生存率较差相关。异位 Gprc5c 表达通过激活 NF-κB 增加 AML 的侵袭性，导致代谢状态改变，细胞内支链氨基酸 (BCAA) 水平升高。Gprc5c 缺失可逆转这种致癌代谢特征，同时消除白血病起始潜能。用 JPH203 靶向 BCAA 转运蛋白 SLC7A5 可抑制氧化磷酸化并产生强烈的抗白血病作用，特别是在小鼠和患者 AML 样本中，同时保留健康的骨髓细胞。在 venetoclax 和阿扎胞苷存在的情况下，这种抗白血病作用得到了加强。我们的研究结果表明，GPRC5C-NF-κB-SLC7A5-BCAA 轴是一个治疗靶点，可以破坏 AML 中的白血病干细胞功能。
