The KRAS-G12D mutation induces metabolic vulnerability in B-cell acute lymphoblastic leukemia

iScience

卷:25

Hui Li¹  Liang Zhu²  Ning Xiao³  Renate Kirschner-Schwabe⁴  Bin-Bing S. Zhou⁵  Alex Toker⁶  Yabin Tang⁶  Ziqing Kong⁷  Houshun Fang⁸  Huiying Sun⁸  Yao Chen⁸  Fan Yang⁸  Yan Xu⁸ 

[1] Correspondence:;

[2] German Cancer Consortium and German Cancer Research Center, Heidelberg, Germany;

[3] Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA;

[4] Charité Universitätsmedizin Berlin, Berlin, Germany;

[5] Clinical Research Center, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China;

[6] 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;

[7] Hangzhou Calibra Diagnostic, Ltd, Hangzhou, China;

[8] 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;

关键词: Biological sciences;    Biochemistry;    Molecular biology;   

DOI  :  

来源: DOAJ

【 摘 要 】

Summary: 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 in vitro 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 in vivo 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.

【 授权许可】

Unknown