Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Mol Immunol. 2020 Sep;125:115-122. doi: 10.1016/j.molimm.2020.06.029. Epub 2020 Jul 10.
Genome-wide association studies have established that human REL is a susceptibility gene for lymphoid cancers and inflammatory diseases. REL is the hematopoietic member of the nuclear factor-κB (NF-κB) family and is frequently amplified in human lymphomas. However, the mechanism through which REL and its encoded protein c-Rel affect human lymphoma is largely unknown. Using both loss-of-function and gain-of-function approaches, we studied the roles of REL gene in human Jurkat leukemia cells. Compared with control Jurkat cells, REL knockout cells exhibited significant defects in cell growth and mitochondrial respiration. Genome-wide transcriptome analyses revealed that T cells lacking c-Rel had selective defects in the expression of inflammatory and metabolic genes including c-Myc. We found that c-Rel controlled the expression of c-Myc through its promotor, and expressing c-Myc in c-Rel-deficient lymphoma cells rescued their proliferative and metabolic defects. Thus, the human c-Rel-c-Myc axis controls lymphoma growth and metabolism and could be a therapeutic target for lymphomas.
全基因组关联研究已经确定人类 REL 是淋巴癌和炎症性疾病的易感基因。REL 是核因子-κB（NF-κB）家族的造血成员，在人类淋巴瘤中经常扩增。然而，REL 和其编码蛋白 c-Rel 影响人类淋巴瘤的机制在很大程度上尚不清楚。我们使用功能丧失和功能获得两种方法，研究了 REL 基因在人类 Jurkat 白血病细胞中的作用。与对照 Jurkat 细胞相比，REL 敲除细胞在细胞生长和线粒体呼吸方面表现出明显缺陷。全基因组转录组分析显示，缺乏 c-Rel 的 T 细胞在炎症和代谢基因的表达上存在选择性缺陷，包括 c-Myc。我们发现 c-Rel 通过其启动子控制 c-Myc 的表达，在缺乏 c-Rel 的淋巴瘤细胞中表达 c-Myc 可挽救其增殖和代谢缺陷。因此，人类 c-Rel-c-Myc 轴控制淋巴瘤的生长和代谢，可能成为淋巴瘤的治疗靶点。
