ORP4L Extracts and Presents PIP2 from Plasma Membrane for PLC beta 3 Catalysis : Targeting It Eradicates Leukemia Stem Cells

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Zhong , W , Xu , M , Li , C , Zhu , B , Cao , X , Li , D , Chen , H , Hu , C , Li , R , Luo , C , Pan , G , Zhang , W , Lai , C , Wang , T , Du , X , Chen , H , Xu , G , Olkkonen , V M , Lei , P , Xu , J & Yan , D 2019 , ' ORP4L Extracts and Presents PIP2 from Plasma Membrane for PLC beta 3 Catalysis : Targeting It Eradicates Leukemia Stem Cells ' , Cell Reports , vol. 26 , no. 8 , pp. 2166-+ . https://doi.org/10.1016/j.celrep.2019.01.082

Title: ORP4L Extracts and Presents PIP2 from Plasma Membrane for PLC beta 3 Catalysis : Targeting It Eradicates Leukemia Stem Cells
Author: Zhong, Wenbin; Xu, Mengyang; Li, Chanjuan; Zhu, Biying; Cao, Xiuye; Li, Dan; Chen, Huanzhao; Hu, Chunxiu; Li, Rong; Luo, Chengwei; Pan, Guoping; Zhang, Wenqiang; Lai, Chaofeng; Wang, Tong; Du, Xin; Chen, Hong; Xu, Guowang; Olkkonen, Vesa M.; Lei, Pingsheng; Xu, Jun; Yan, Daoguang
Contributor: University of Helsinki, Medicum
Date: 2019-02-19
Language: eng
Number of pages: 21
Belongs to series: Cell Reports
ISSN: 2211-1247
URI: http://hdl.handle.net/10138/299984
Abstract: 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 PLC beta 3, enabling IP3 generation and subsequentCa(2+)-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.
Subject: MOLECULAR-DYNAMICS SIMULATIONS
ACUTE MYELOID-LEUKEMIA
BINDING PROTEIN
CANCER
AMBER
ACTIVATION
TRANSPORT
HALLMARKS
OSW-1
3111 Biomedicine
1182 Biochemistry, cell and molecular biology
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