Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
TranslaTUM, Center for Translational Cancer Research, Technical University of Munich, Munich, Germany.
J Exp Med. 2021 Feb 1;218(2). doi: 10.1084/jem.20200517.
Clinical evidence suggests alterations in receptor activator of NF-κB (RANK) signaling are key contributors to B cell autoimmunity and malignancy, but the pathophysiological consequences of aberrant B cell-intrinsic RANK signaling remain unknown. We generated mice that express a human lymphoma-derived, hyperactive RANKK240E variant in B lymphocytes in vivo. Forced RANK signaling disrupted B cell tolerance and induced a fully penetrant systemic lupus erythematosus-like disease in addition to the development of chronic lymphocytic leukemia (CLL). Importantly, RANKK240E transgenic CLL cells as well as CLL cells of independent murine and of human origin depend on microenvironmental RANK ligand (RANKL) for tumor cell survival. Consequently, inhibition of the RANKL-RANK axis with anti-RANKL antibodies killed murine and human CLL cells in vitro and in vivo. These results establish pathological B cell-intrinsic RANK signaling as a potential driver of autoimmunity and B cell malignancy, and they suggest the exploitation of clinically available anti-RANKL compounds for CLL treatment.
临床证据表明，核因子-κB 受体激活剂（RANK）信号的改变是 B 细胞自身免疫和恶性肿瘤的关键因素，但异常的 B 细胞内在 RANK 信号的病理生理后果尚不清楚。我们生成了在体内表达 B 淋巴细胞中人类淋巴瘤衍生的、高活性 RANKK240E 变体的小鼠。强制 RANK 信号破坏了 B 细胞耐受，并诱导了完全穿透的系统性红斑狼疮样疾病，此外还发展了慢性淋巴细胞白血病（CLL）。重要的是，RANKK240E 转基因 CLL 细胞以及独立的小鼠和人类来源的 CLL 细胞依赖于微环境中的 RANK 配体（RANKL）来维持肿瘤细胞的存活。因此，用抗 RANKL 抗体抑制 RANKL-RANK 轴在体外和体内杀死了小鼠和人类的 CLL 细胞。这些结果确立了病理性 B 细胞内在 RANK 信号作为自身免疫和 B 细胞恶性肿瘤的潜在驱动因素，并表明可以利用临床可用的抗 RANKL 化合物来治疗 CLL。
