The mA reader IGF2BP2 regulates glutamine metabolism and represents a therapeutic target in acute myeloid leukemia.

Johanna Ten Hoeve, Ying Yang, Li Han, Subo Zhang, Yuelong Ma, Mingli Sun, Huizhe Wu, Zheng Zhang, Daniel Braas, Jingwen Li, Bin Zhang, Guido Marcucci, Keda Zhou, Hong-Fang Tao, Minjie Wei, Huilin Huang, Jianjun Chen, Hengyou Weng, Mark Wunderlich, Hongzhi Li, Sean Robinson, Emily Prince, Wei Li, Zhenhua Chen, James C Mulloy, David Horne, Xiaolan Deng, Feng Huang, Zhaojin Yu, Yalin Kang, Keren Zhou, Jiacheng Hu, Chen Fu, Tursunjan Aziz

Journal: Cancer cell 2022;40(12):1566-1582.e10

PMID: 36306790

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Abstract

N-Methyladenosine (mA) modification and its modulators play critical roles and show promise as therapeutic targets in human cancers, including acute myeloid leukemia (AML). IGF2BP2 was recently reported as an mA binding protein that enhances mRNA stability and translation. However, its function in AML remains largely elusive. Here we report the oncogenic role and the therapeutic targeting of IGF2BP2 in AML. High expression of IGF2BP2 is observed in AML and associates with unfavorable prognosis. IGF2BP2 promotes AML development and self-renewal of leukemia stem/initiation cells by regulating expression of critical targets (e.g., MYC, GPT2, and SLC1A5) in the glutamine metabolism pathways in an mA-dependent manner. Inhibiting IGF2BP2 with our recently identified small-molecule compound (CWI1-2) shows promising anti-leukemia effects in vitro and in vivo. Collectively, our results reveal a role of IGF2BP2 and mA modification in amino acid metabolism and highlight the potential of targeting IGF2BP2 as a promising therapeutic strategy in AML.

Address: The Fifth Affiliated Hospital, State Key Laboratory of Respiratory Diseases, Guangzhou Laboratory, Guangzhou Medical University, Guangzhou 510005, China; Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; Bioland Laboratory, Guangzhou 51005, China. Electronic address: [email protected].; The Fifth Affiliated Hospital, State Key Laboratory of Respiratory Diseases, Guangzhou Laboratory, Guangzhou Medical University, Guangzhou 510005, China; Bioland Laboratory, Guangzhou 51005, China.; Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning 110122, China.; Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA.; Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.; Bioland Laboratory, Guangzhou 51005, China; Shantou University Medical College, Shantou 515063, China.; Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning 110122, China.; Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.; Bioland Laboratory, Guangzhou 51005, China.; Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.; UCLA Metabolomics Center, Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA.; Department of Hematologic Malignancies Translational Science, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; Gehr Family Center for Leukemia Research & City of Hope Comprehensive Cancer Center, City of Hope, Duarte, CA 91010, USA.; School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong SAR, China.; Department of Hematology, The First Affiliated Hospital of Shantou University Medical College, Shantou 515041, China.; Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning 110122, China. Electronic address: [email protected].; Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China; Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA. Electronic address: [email protected].; Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; Gehr Family Center for Leukemia Research & City of Hope Comprehensive Cancer Center, City of Hope, Duarte, CA 91010, USA. Electronic address: [email protected].

DOI: 10.1016/j.ccell.2022.10.004

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MeSH Terms: Humans, Glutamine, Leukemia, Myeloid, Acute, RNA Stability, Prognosis, Minor Histocompatibility Antigens, Amino Acid Transport System ASC, RNA-Binding Proteins