Transcriptome analysis of G protein-coupled receptors in distinct genetic subgroups of acute myeloid leukemia: identification of potential disease-specific targets.

A Maiga,M Bouvier,J Hébert,G Sauvageau,V-P Lavallée,C Pabst,S Lemieux

doi:10.1038/bcj.2016.36

Abstract

Acute myeloid leukemia (AML) is associated with poor clinical outcome and the development of more effective therapies is urgently needed. G protein-coupled receptors (GPCRs) represent attractive therapeutic targets, accounting for approximately 30% of all targets of marketed drugs. Using next-generation sequencing, we studied the expression of 772 GPCRs in 148 genetically diverse AML specimens, normal blood and bone marrow cell populations as well as cord blood-derived CD34-positive cells. Among these receptors, 30 are overexpressed and 19 are downregulated in AML samples compared with normal CD34-positive cells. Upregulated GPCRs are enriched in chemokine (CCR1, CXCR4, CCR2, CX3CR1, CCR7 and CCRL2), adhesion (CD97, EMR1, EMR2 and GPR114) and purine (including P2RY2 and P2RY13) receptor subfamilies. The downregulated receptors include adhesion GPCRs, such as LPHN1, GPR125, GPR56, CELSR3 and GPR126, protease-activated receptors (F2R and F2RL1) and the Frizzled family receptors SMO and FZD6. Interestingly, specific deregulation was observed in genetically distinct subgroups of AML, thereby identifying different potential therapeutic targets in these frequent AML subgroups.

Highlights

G protein-coupled receptors (GPCRs) represent the largest family of membrane receptors with an estimated number of 800 members in human
Using RNA Sequencing (RNA-Seq), we have evaluated the expression of GPCRs in 148 Acute myeloid leukemia (AML) samples and compared it with that observed in normal cord blood-derived CD34+CD45RA− hematopoietic stem and progenitor cells and in normal bone marrow and peripheral blood cell populations
Our results revealed that 30 GPCRs are overexpressed in AML samples compared with normal CD34+ cells

Summary

Introduction

G protein-coupled receptors (GPCRs) represent the largest family of membrane receptors with an estimated number of 800 members in human. They are key transducers that bind a vast diversity of ligands allowing the cells to adapt to their environment by regulating a wide variety of physiological processes including the control of blood pressure, heart rate, digestive processes, hormone secretion, cell growth and migration as well as vision and olfaction. Several GPCRs are critical for cell proliferation and survival, and can be aberrantly expressed in cancer cells.[3,4] For example, PAR1 is overexpressed in invasive breast carcinomas[5] or advanced-stage prostate cancer.[6,7] Likewise, the chemokine receptor CXCR4 has an important role in tumor metastasis and angiogenesis.[3,4] the Wnt target gene, Lgr[5], identified as a marker of intestinal stem cells, is implicated in mouse intestinal tumorigenesis[8,9] and its expression is associated with poor clinical outcome in colorectal cancer.[10]

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