title: Acidosis Sensing Receptor GPR65 Correlates with Anti-Apoptotic Bcl-2 Family Member Expression in CLL Cells: Potential Implications for the CLL Microenvironment.
abstract: The tumor microenvironment is generally an acidic environment, yet the effect of extracellular acidosis on chronic lymphocytic leukemia (CLL) is not well established. Here we are the first to report that the extracellular acid sensing G-protein coupled receptor, GPR65, is expressed in primary CLL cells where its level correlate strongly with anti-apoptotic Bcl-2 family member levels. GPR65 expression is found normally within the lymphoid lineage and has not been previously reported in CLL. We demonstrate a wide range of GPR65 mRNA expression among CLL 87 patient samples. The correlation between GPR65 mRNA levels and Bcl-2 mRNA levels is particularly strong (r=0.8063, p= <0.001). The correlation extends to other anti-apoptotic Bcl-2 family members, Mcl-1 (r=0.4847, p=0.0010) and Bcl-xl (r=0.3411, p=0.0252), although at lower levels of significance. No correlation is detected between GPR65 and levels of the pro-apoptotic proteins BIM, PUMA or NOXA. GPR65 expression also correlates with the favorable prognostic marker of 13q deletion. The present findings suggest the acid sensing receptor GPR65 may be of significance to allow CLL tolerance of extracellular acidosis. The correlation of GPR65 with Bcl-2 suggests a novel cytoprotective mechanism that enables CLL cell adaptation to acidic extracellular conditions. These findings suggest the potential value of targeting GPR65 therapeutically.
authors.affiliation: Division of Hematology-Oncology, University Hospitals Case Medical Center, Cleveland, Ohio, USA ; Division of Hematology, Department of Medicine, Ohio State University College of Medicine, Columbus, Ohio, USA.
authors.forename: Ashley E
authors.initials: AE
authors.lastname: Rosko
authors.affiliation: Division of Hematology-Oncology, Case Western Reserve School of Medicine, Cleveland, USA.
authors.forename: Karen S
authors.initials: KS
authors.lastname: McColl
authors.affiliation: Division of Hematology-Oncology, Case Western Reserve School of Medicine, Cleveland, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Zhong
authors.affiliation: Division of Hematology-Oncology, Case Western Reserve School of Medicine, Cleveland, USA.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Ryder
authors.affiliation: Division of Hematology-Oncology, Case Western Reserve School of Medicine, Cleveland, USA.
authors.forename: Ming-Jin
authors.initials: MJ
authors.lastname: Chang
authors.affiliation: Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Abdus
authors.initials: A
authors.lastname: Sattar
authors.affiliation: Division of Hematology-Oncology, University Hospitals Case Medical Center, Cleveland, Ohio, USA ; Division of Hematology-Oncology, Case Western Reserve School of Medicine, Cleveland, USA ; Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Ohio, USA.
authors.forename: Paolo F
authors.initials: PF
authors.lastname: Caimi
authors.affiliation: Department of Hematologic Oncology and Blood Disorders, Cleveland Clinic, Cleveland, Ohio, USA ; Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Ohio, USA.
authors.forename: Brian T
authors.initials: BT
authors.lastname: Hill
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Sayer
authors.initials: S
authors.lastname: Al-Harbi
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA ; Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Ohio, USA.
authors.forename: Alexandru
authors.initials: A
authors.lastname: Almasan
authors.affiliation: Division of Hematology-Oncology, University Hospitals Case Medical Center, Cleveland, Ohio, USA ; Division of Hematology-Oncology, Case Western Reserve School of Medicine, Cleveland, USA ; Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Ohio, USA.
authors.forename: Clark W
authors.initials: CW
authors.lastname: Distelhorst
keywords: Chronic lymphocytic leukemia; GPR65G protein-coupled receptor 65 Bcl-2B-cell Lymphoma 2; Microenvironment; TDAG8T cell death associated gene