The KRAS-G12D mutation induces metabolic vulnerability in B-cell acute lymphoblastic leukemia
Yan Xu,
Houshun Fang,
Yao Chen,
Yabin Tang,
Huiying Sun,
Ziqing Kong,
Fan Yang,
Renate Kirschner-Schwabe,
Liang Zhu,
Alex Toker,
Ning Xiao,
Bin-Bing S. Zhou,
Hui Li
Affiliations
Yan Xu
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
Houshun Fang
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
Yao Chen
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
Yabin Tang
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
Huiying Sun
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
Ziqing Kong
Hangzhou Calibra Diagnostic, Ltd, Hangzhou, China
Fan Yang
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
Renate Kirschner-Schwabe
Charité Universitätsmedizin Berlin, Berlin, Germany; German Cancer Consortium and German Cancer Research Center, Heidelberg, Germany
Liang Zhu
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
Alex Toker
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA
Ning Xiao
Clinical Research Center, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China; Correspondence:
Bin-Bing S. Zhou
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; Fujian Children’s Hospital, Fujian Branch of Shanghai Children's Medical Center Affiliated to Shanghai Jiaotong University School of Medicine, Fujian, 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; Corresponding author
Hui Li
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; Fujian Children’s Hospital, Fujian Branch of Shanghai Children's Medical Center Affiliated to Shanghai Jiaotong University School of Medicine, Fujian, 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; Corresponding author
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.
