Xu Yan, Fang Houshun, Chen Yao, Tang Yabin, Sun Huiying, Kong Ziqing, Yang Fan, Kirschner-Schwabe Renate, Zhu Liang, Toker Alex, Xiao Ning, Zhou Bin-Bing S, Li Hui
Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Department of Pharmacology and Chemical Biology, School of Basic Medicine and Collaborative Innovation Center for Translational Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
iScience. 2022 Feb 7;25(3):103881. doi: 10.1016/j.isci.2022.103881. eCollection 2022 Mar 18.
Mutations in RAS pathway genes are highly prevalent in acute lymphoblastic leukemia (ALL). However, the effects of RAS mutations on ALL cell growth have not been experimentally characterized, and effective RAS-targeting therapies are being sought after. Here, we found that Reh ALL cells bearing the KRAS-G12D mutation showed increased proliferation rates but displayed severely compromised growth in mice. Exploring this divergence, proliferation assays with multiple ALL cell lines revealed that the KRAS-G12D rewired methionine and arginine metabolism. Isotope tracing results showed that KRAS-G12D promotes catabolism of methionine and arginine to support anabolism of polyamines and proline, respectively. Chemical inhibition of polyamine biosynthesis selectively killed KRAS-G12D B-ALL cells. Finally, chemically inhibiting AKT/mTOR signaling abrogated the altered amino acid metabolism and strongly promoted the growth of KRAS-G12D cells in B-ALL xenograft. Our study thus illustrates how hyperactivated AKT/mTOR signaling exerts distinct impacts on hematological malignancies vs. solid tumors.
RAS通路基因的突变在急性淋巴细胞白血病（ALL）中非常普遍。然而，RAS突变对ALL细胞生长的影响尚未通过实验进行表征，目前正在寻找有效的RAS靶向疗法。在这里，我们发现携带KRAS-G12D突变的Reh ALL细胞显示出增殖率增加，但在小鼠体内生长严重受损。为了探究这种差异，我们对多个ALL细胞系进行了增殖试验，结果显示KRAS-G12D改变了蛋氨酸和精氨酸的代谢。同位素示踪结果表明，KRAS-G12D分别促进蛋氨酸和精氨酸的分解代谢，以支持多胺和脯氨酸的合成代谢。化学抑制多胺生物合成可选择性杀死KRAS-G12D B-ALL细胞。最后，化学抑制AKT/mTOR信号通路消除了氨基酸代谢的改变，并强烈促进了KRAS-G12D细胞在B-ALL异种移植中的生长。因此，我们的研究阐明了过度激活的AKT/mTOR信号通路如何对血液系统恶性肿瘤和实体瘤产生不同的影响。
