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; Daoguang Yan

doi:10.1038/ncomms12702

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, Daoguang Yan

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58 Scopus citations

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 CD3ϵ, Gα_q/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.

Original language	English (US)
Article number	12702
Journal	Nature Communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms12702
State	Published - Sep 1 2016

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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10.1038/ncomms12702

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@article{5a507a2d2de545c6bf07fba8eb329215,

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 CD3ϵ, 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.",

author = "Wenbin Zhong and Qing Yi and Bing Xu and Shiqian Li and Tong Wang and Fupei Liu and Biying Zhu and Hoffmann, {Peter R.} and Guangju Ji and Pingsheng Lei and Guoping Li and Jiwei Li and Jian Li and Olkkonen, {Vesa M.} and Daoguang Yan",

note = "Funding Information: This work was supported by grants from National Basic Research Program of China (2012CB517502 to D.Y.), from Major Research plan of the National Natural Science Foundation of China (91439122 to D.Y.), from NSFC, China (Grant 30971104 to D.Y.), by the Academy of Finland (Grant 285223 to V.M.O.), the Sigrid Juselius Foundation, the Magnus Ehrnrooth Foundation and the Finnish Foundation for Cardiovascular Research (V.M.O.).",

year = "2016",

month = sep,

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doi = "10.1038/ncomms12702",

language = "English (US)",

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T1 - ORP4L is essential for T-cell acute lymphoblastic leukemia cell survival

AU - Zhong, Wenbin

AU - Yi, Qing

AU - Xu, Bing

AU - Li, Shiqian

AU - Wang, Tong

AU - Liu, Fupei

AU - Zhu, Biying

AU - Hoffmann, Peter R.

AU - Ji, Guangju

AU - Lei, Pingsheng

AU - Li, Guoping

AU - Li, Jiwei

AU - Li, Jian

AU - Olkkonen, Vesa M.

AU - Yan, Daoguang

N1 - Funding Information: This work was supported by grants from National Basic Research Program of China (2012CB517502 to D.Y.), from Major Research plan of the National Natural Science Foundation of China (91439122 to D.Y.), from NSFC, China (Grant 30971104 to D.Y.), by the Academy of Finland (Grant 285223 to V.M.O.), the Sigrid Juselius Foundation, the Magnus Ehrnrooth Foundation and the Finnish Foundation for Cardiovascular Research (V.M.O.).

PY - 2016/9/1

Y1 - 2016/9/1

N2 - 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 CD3ϵ, 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.

AB - 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 CD3ϵ, 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.

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

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