ORP4L Extracts and Presents PIP2 from Plasma Membrane for PLCβ3 Catalysis: Targeting It Eradicates Leukemia Stem Cells
Wenbin Zhong,
Mengyang Xu,
Chanjuan Li,
Biying Zhu,
Xiuye Cao,
Dan Li,
Huanzhao Chen,
Chunxiu Hu,
Rong Li,
Chengwei Luo,
Guoping Pan,
Wenqiang Zhang,
Chaofeng Lai,
Tong Wang,
Xin Du,
Hong Chen,
Guowang Xu,
Vesa M. Olkkonen,
Pingsheng Lei,
Jun Xu,
Daoguang Yan
Affiliations
Wenbin Zhong
Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Department of Biology, Jinan University, Guangzhou 510632, China
Mengyang Xu
Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China
Chanjuan Li
Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China
Biying Zhu
Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Department of Biology, Jinan University, Guangzhou 510632, China
Xiuye Cao
Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Department of Biology, Jinan University, Guangzhou 510632, China
Dan Li
Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Department of Biology, Jinan University, Guangzhou 510632, China
Huanzhao Chen
Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Department of Biology, Jinan University, Guangzhou 510632, China
Chunxiu Hu
CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Science, Dalian 116011, China
Rong Li
Department of Hematology, Chang Zheng Hospital, Shanghai 200003, China
Chengwei Luo
Department of Hematology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510000, China
Guoping Pan
Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Department of Biology, Jinan University, Guangzhou 510632, China
Wenqiang Zhang
Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Department of Biology, Jinan University, Guangzhou 510632, China
Chaofeng Lai
Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Department of Biology, Jinan University, Guangzhou 510632, China
Tong Wang
Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Department of Biology, Jinan University, Guangzhou 510632, China
Xin Du
Department of Hematology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510000, China
Hong Chen
Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
Guowang Xu
CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Science, Dalian 116011, China
Vesa M. Olkkonen
Minerva Foundation Institute for Medical Research, Biomedicum 2U, Helsinki 00290, Finland; Department of Anatomy, Faculty of Medicine, University of Helsinki, Helsinki 00014, Finland
Pingsheng Lei
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Chinese Academy of Medical Sciences, Beijing 100050, China
Jun Xu
Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China
Daoguang Yan
Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Department of Biology, Jinan University, Guangzhou 510632, China; Corresponding author
Summary: Leukemia stem cells (LSCs) are a rare subpopulation of abnormal hematopoietic stem cells (HSCs) that propagates leukemia and are responsible for the high frequency of relapse in therapies. Detailed insights into LSCs’ survival will facilitate the identification of targets for therapeutic approaches. Here, we develop an inhibitor, LYZ-81, which targets ORP4L with high affinity and specificity and selectively eradicates LCSs in vitro and in vivo. ORP4L is expressed in LSCs but not in normal HSCs and is essential for LSC bioenergetics and survival. It extracts PIP2 from the plasma membrane and presents it to PLCβ3, enabling IP3 generation and subsequent Ca2+-dependent bioenergetics. LYZ-81 binds ORP4L competitively with PIP2 and blocks PIP2 hydrolysis, resulting in defective Ca2+ signaling. The results provide evidence that LSCs can be eradicated through the inhibition of ORP4L by LYZ-81, which may serve as a starting point of drug development for the elimination of LSCs to eventually cure leukemia. : Zhong et al. report that abnormal expression of ORP4L is essential for leukemia stem cell survival; it enables IP3 generation by extracting and presenting PIP2 from the plasma membrane to PLCβ3 for hydrolysis. The compound LYZ-81, which blocks this process via targeting ORP4L, selectively eradicates leukemia stem cells. Keywords: leukemia stem cell, OSBP-related protein 4L, PIP2 hydrolysis, Ca2+ signaling, energy metabolism, therapy
