Division of Tumor and Cellular Biochemistry, Department of Medical Science, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
Leukemia. 2013 Aug;27(8):1637-49. doi: 10.1038/leu.2013.75. Epub 2013 Mar 12.
Acute myeloid leukemia with high ecotropic viral integration site-1 expression (EVI1(high) AML) is classified as a refractory type of leukemia with a poor prognosis. To provide new insights into the prevention and treatment of this disease, we identified the high expression of EVI1-regulated G protein-coupled receptor 56 (GPR56), and the association of high cell adhesion and antiapoptotic activities in EVI1(high) AML cells. Knockdown of GPR56 expression decreased the cellular adhesion ability through inactivation of RhoA signaling, resulting in a reduction of cellular growth rates and enhanced apoptosis. Moreover, in Gpr56(-/-) mice, the number of hematopoietic stem cells (HSCs) was significantly decreased in the bone marrow (BM) and, conversely, was increased in the spleen, liver and peripheral blood. The number of Gpr56(-/-) HSC progenitors in the G0/G1-phase was significantly reduced and was associated with impaired cellular adhesion. Finally, the loss of GPR56 function resulted in a reduction of the in vivo repopulating ability of the HSCs. In conclusion, GPR56 may represent an important GPCR for the maintenance of HSCs by acting as a co-ordinator of interactions with the BM osteosteal niche; furthermore, this receptor has the potential to become a novel molecular target in EVI1(high) leukemia.
高表达嗜酸性病毒整合位点 1 的急性髓系白血病（EVI1(high) AML）被归类为难治性白血病，预后不良。为了深入了解这种疾病的预防和治疗，我们发现 EVI1 调控的 G 蛋白偶联受体 56（GPR56）在 EVI1(high) AML 细胞中高表达，并与高细胞黏附和抗凋亡活性相关。GPR56 表达的敲低通过失活 RhoA 信号降低了细胞黏附能力，导致细胞生长速率降低和凋亡增强。此外，在 Gpr56(-/-) 小鼠中，骨髓中的造血干细胞（HSCs）数量显著减少，而脾脏、肝脏和外周血中的 HSCs 数量则增加。Gpr56(-/-) HSC 祖细胞在 G0/G1 期的数量明显减少，与细胞黏附受损有关。最后，GPR56 功能的丧失导致 HSCs 的体内重编程能力降低。总之，GPR56 可能通过作为与 BM 成骨龛相互作用的协调因子，代表维持 HSCs 的重要 GPCR；此外，该受体有可能成为 EVI1(high) 白血病的新分子靶点。
