title: ORP4L is essential for T-cell acute lymphoblastic leukemia cell survival.
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 Ca(2+) 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.
authors: Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Department of Biotechnology, College of Life Science and Technology, Jinan University, Guangzhou 510632, China.
authors: Wenbin
authors: W
authors: Zhong
authors: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors: Qing
authors: Q
authors: Yi
authors: Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors: Bing
authors: B
authors: Xu
authors: Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Department of Biotechnology, College of Life Science and Technology, Jinan University, Guangzhou 510632, China.
authors: Shiqian
authors: S
authors: Li
authors: Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Department of Biotechnology, College of Life Science and Technology, Jinan University, Guangzhou 510632, China.
authors: Tong
authors: T
authors: Wang
authors: Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Department of Biotechnology, College of Life Science and Technology, Jinan University, Guangzhou 510632, China.
authors: Fupei
authors: F
authors: Liu
authors: Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Department of Biotechnology, College of Life Science and Technology, Jinan University, Guangzhou 510632, China.
authors: Biying
authors: B
authors: Zhu
authors: Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii 96813, USA.
authors: Peter R
authors: PR
authors: Hoffmann
authors: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors: Guangju
authors: G
authors: Ji
authors: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Chinese Academy of Medical Sciences, Beijing 100050, China.
authors: Pingsheng
authors: P
authors: Lei
authors: The Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology &Beijing Institute of Geriatrics, Ministry of Health, Beijing 100730, China.
authors: Guoping
authors: G
authors: Li
authors: Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Department of Biotechnology, College of Life Science and Technology, Jinan University, Guangzhou 510632, China.
authors: Jiwei
authors: J
authors: Li
authors: The Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology &Beijing Institute of Geriatrics, Ministry of Health, Beijing 100730, China.
authors: Jian
authors: J
authors: Li
authors: Minerva Foundation Institute for Medical Research, Biomedicum 2U, Helsinki FI-00290, Finland.
authors: Vesa M
authors: VM
authors: Olkkonen
authors: Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Department of Biotechnology, College of Life Science and Technology, Jinan University, Guangzhou 510632, China.
authors: Daoguang
authors: D
authors: Yan
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005260:Female; D006801:Humans; D019169:Jurkat Cells; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008928:Mitochondria / Q000378:metabolism; D010085:Oxidative Phosphorylation; D054799:Phospholipase C beta / Q000378:metabolism*; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology*; D011987:Receptors, Steroid / Q000096:biosynthesis*; D013601:T-Lymphocytes / Q000378:metabolism; D000098825:Oxysterol Binding Proteins
chemical_list: D011987:Receptors, Steroid; D000098825:Oxysterol Binding Proteins; D000255:Adenosine Triphosphate; C518039:PLCB3 protein, human; D054799:Phospholipase C beta; D002118:Calcium