ORP4L is essential for T-cell acute lymphoblastic leukemia cell survival

Wenbin Zhong, Qing Yi, Bing Xu, Shiqian Li, Tong Wang, Fupei Liu, Biying Zhu, Peter R. Hoffmann, Guangju Ji, Pingsheng Lei, Guoping Li, Jiwei Li, Jian Li, Vesa M. Olkkonen and Daoguang Yan ()
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Wenbin Zhong: Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, College of Life Science and Technology, Jinan University
Qing Yi: Lerner Research Institute, Cleveland Clinic
Bing Xu: Nanfang Hospital, Southern Medical University
Shiqian Li: Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, College of Life Science and Technology, Jinan University
Tong Wang: Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, College of Life Science and Technology, Jinan University
Fupei Liu: Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, College of Life Science and Technology, Jinan University
Biying Zhu: Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, College of Life Science and Technology, Jinan University
Peter R. Hoffmann: John A. Burns School of Medicine, University of Hawaii
Guangju Ji: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences
Pingsheng Lei: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Chinese Academy of Medical Sciences
Guoping Li: The Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology & Beijing Institute of Geriatrics, Ministry of Health
Jiwei Li: Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, College of Life Science and Technology, Jinan University
Jian Li: The Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology & Beijing Institute of Geriatrics, Ministry of Health
Vesa M. Olkkonen: Minerva Foundation Institute for Medical Research
Daoguang Yan: Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, College of Life Science and Technology, Jinan University

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: Abstract Metabolic pathways are reprogrammed in cancer to support cell survival. Here, we report that T-cell acute lymphoblastic leukemia (T-ALL) cells are characterized by increased oxidative phosphorylation and robust ATP production. We demonstrate that ORP4L is expressed in T-ALL but not normal T-cells and its abundance is proportional to cellular ATP. ORP4L acts as an adaptor/scaffold assembling CD3ɛ, Gαq/11 and PLCβ3 into a complex that activates PLCβ3. PLCβ3 catalyzes IP3 production in T-ALL as opposed to PLCγ1 in normal T-cells. Up-regulation of ORP4L thus results in a switch in the enzyme responsible for IP3-induced endoplasmic reticulum Ca2+ release and oxidative phosphorylation. ORP4L knockdown results in suboptimal bioenergetics, cell death and abrogation of T-ALL engraftment in vivo. In summary, we uncovered a signalling pathway operating specifically in T-ALL cells in which ORP4L mediates G protein-coupled ligand-induced PLCβ3 activation, resulting in an increase of mitochondrial respiration for cell survival. Targeting ORP4L might represent a promising approach for T-ALL treatment.

Date: 2016
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DOI: 10.1038/ncomms12702

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