ORP4L Extracts and Presents PIP from Plasma Membrane for PLCβ3 Catalysis: Targeting It Eradicates Leukemia Stem Cells.

Authors:
Wenbin Zhong
Wenbin Zhong
Jinan University
China
Chanjuan Li
Chanjuan Li
Fourth Military Medical University
China
Biying Zhu
Biying Zhu
Jinan University
Xiuye Cao
Xiuye Cao
College of Life Science and Technology
Guangzhou Shi | China
Huanzhao Chen
Huanzhao Chen
Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes
Chunxiu Hu
Chunxiu Hu
CAS Key Laboratory of Separation Science for Analytical Chemistry
China

Cell Rep 2019 Feb;26(8):2166-2177.e9

Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Department of Biology, Jinan University, Guangzhou 510632, China. Electronic address:

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 PIP from the plasma membrane and presents it to PLCβ3, enabling IP generation and subsequent Ca-dependent bioenergetics. LYZ-81 binds ORP4L competitively with PIP and blocks PIP hydrolysis, resulting in defective Ca 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.

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http://dx.doi.org/10.1016/j.celrep.2019.01.082DOI Listing
February 2019
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