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

Research output: Contribution to journalArticle

29 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, 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.

Original languageEnglish (US)
Article number12702
JournalNature Communications
Volume7
DOIs
StatePublished - Sep 1 2016

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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