Rosko Ashley E, McColl Karen S, Zhong Fei, Ryder Christopher B, Chang Ming-Jin, Sattar Abdus, Caimi Paolo F, Hill Brian T, Al-Harbi Sayer, Almasan Alexandru, Distelhorst Clark W
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.
Division of Hematology-Oncology, Case Western Reserve School of Medicine, Cleveland, USA.
J Leuk (Los Angel). 2014 Dec;2(5). doi: 10.4172/2329-6917.1000160.
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.
肿瘤微环境通常是酸性环境，但细胞外酸中毒对慢性淋巴细胞白血病（CLL）的影响尚未完全明确。在此，我们首次报道细胞外酸敏感的G蛋白偶联受体GPR65在原发性CLL细胞中表达，其水平与抗凋亡Bcl-2家族成员水平密切相关。GPR65的表达通常在淋巴谱系中被发现，此前在CLL中尚未见报道。我们在87例CLL患者样本中检测到GPR65 mRNA表达范围广泛。GPR65 mRNA水平与Bcl-2 mRNA水平之间的相关性尤为显著（r = 0.8063，p = <0.001）。这种相关性也延伸至其他抗凋亡Bcl-2家族成员，Mcl-1（r = 0.4847，p = 0.0010）和Bcl-xl（r = 0.3411，p = 0.0252），尽管显著性水平较低。未检测到GPR65与促凋亡蛋白BIM、PUMA或NOXA水平之间的相关性。GPR65表达还与13q缺失这一有利的预后标志物相关。目前的研究结果表明，酸敏感受体GPR65可能对CLL耐受细胞外酸中毒具有重要意义。GPR65与Bcl-2的相关性提示了一种新的细胞保护机制，使CLL细胞能够适应酸性细胞外环境。这些发现提示了靶向GPR65进行治疗的潜在价值。
