The m6A reader IGF2BP2 regulates glutamine metabolism and represents a therapeutic target in acute myeloid leukemia

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

doi:10.1016/j.ccell.2022.10.004

The m⁶A reader IGF2BP2 regulates glutamine metabolism and represents a therapeutic target in acute myeloid leukemia

Cancer Cell. 2022 Dec 12;40(12):1566-1582.e10. doi: 10.1016/j.ccell.2022.10.004. Epub 2022 Oct 27.

Authors

Hengyou Weng¹, Feng Huang², Zhaojin Yu³, Zhenhua Chen⁴, Emily Prince⁴, Yalin Kang⁵, Keren Zhou⁴, Wei Li⁴, Jiacheng Hu⁶, Chen Fu⁷, Tursunjan Aziz⁵, Hongzhi Li⁸, Jingwen Li⁹, Ying Yang², Li Han⁴, Subo Zhang⁵, Yuelong Ma⁸, Mingli Sun³, Huizhe Wu³, Zheng Zhang⁴, Mark Wunderlich¹⁰, Sean Robinson⁴, Daniel Braas¹¹, Johanna Ten Hoeve¹¹, Bin Zhang¹², Guido Marcucci¹², James C Mulloy¹⁰, Keda Zhou¹³, Hong-Fang Tao¹⁴, Xiaolan Deng⁴, David Horne⁸, Minjie Wei¹⁵, Huilin Huang¹⁶, Jianjun Chen¹⁷

Affiliations

¹ 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: weng_hengyou@gzlab.ac.cn.
² The Fifth Affiliated Hospital, State Key Laboratory of Respiratory Diseases, Guangzhou Laboratory, Guangzhou Medical University, Guangzhou 510005, China; Bioland Laboratory, Guangzhou 51005, China.
³ 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.
⁴ Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA.
⁵ Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
⁶ Bioland Laboratory, Guangzhou 51005, China; Shantou University Medical College, Shantou 515063, China.
⁷ Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning 110122, China.
⁸ Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
⁹ Bioland Laboratory, Guangzhou 51005, China.
¹⁰ Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
¹¹ UCLA Metabolomics Center, Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹² 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.
¹³ School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong SAR, China.
¹⁴ Department of Hematology, The First Affiliated Hospital of Shantou University Medical College, Shantou 515041, China.
¹⁵ Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning 110122, China. Electronic address: mjwei@cmu.edu.cn.
¹⁶ 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: huanghl1@sysucc.org.cn.
¹⁷ 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: jianchen@coh.org.

Abstract

N⁶-Methyladenosine (m⁶A) 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 m⁶A 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 m⁶A-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 m⁶A modification in amino acid metabolism and highlight the potential of targeting IGF2BP2 as a promising therapeutic strategy in AML.

Keywords: GPT2; IGF2BP2; MYC; SLC1A5; acute myeloid leukemia; glutamine metabolism; leukemia stem cells; m(6)A modification; mitochondria oxygen consumption; targeted therapy.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Amino Acid Transport System ASC / genetics
Amino Acid Transport System ASC / metabolism
Glutamine* / metabolism
Humans
Leukemia, Myeloid, Acute* / drug therapy
Leukemia, Myeloid, Acute* / genetics
Leukemia, Myeloid, Acute* / metabolism
Minor Histocompatibility Antigens
Prognosis
RNA Stability
RNA-Binding Proteins / genetics
RNA-Binding Proteins / metabolism

Substances

Glutamine
SLC1A5 protein, human
Minor Histocompatibility Antigens
Amino Acid Transport System ASC
IGF2BP2 protein, human
RNA-Binding Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding