Department of Hematology, Leiden University Medical Center, Leiden, Netherlands.
BIOCEV, First Faculty of Medicine, Charles University , Prague, Czech Republic.
J Exp Med. 2024 May 6;221(5). doi: 10.1084/jem.20230941. Epub 2024 Mar 21.
Diffuse large B cell lymphoma of activated B cell type (ABC-DLBCL), a major cell-of-origin DLBCL subtype, is characterized by chronic active B cell receptor (BCR) signaling and NF-κB activation, which can be explained by activating mutations of the BCR signaling cascade in a minority of cases. We demonstrate that autonomous BCR signaling, akin to its essential pathogenetic role in chronic lymphocytic leukemia (CLL), can explain chronic active BCR signaling in ABC-DLBCL. 13 of 18 tested DLBCL-derived BCR, including 12 cases selected for expression of IgM, induced spontaneous calcium flux and increased phosphorylation of the BCR signaling cascade in murine triple knockout pre-B cells without antigenic stimulation or external BCR crosslinking. Autonomous BCR signaling was associated with IgM isotype, dependent on somatic BCR mutations and individual HCDR3 sequences, and largely restricted to non-GCB DLBCL. Autonomous BCR signaling represents a novel immunological oncogenic driver mechanism in DLBCL originating from individual BCR sequences and adds a new dimension to currently proposed genetics- and transcriptomics-based DLBCL classifications.
活化 B 细胞型弥漫性大 B 细胞淋巴瘤（ABC-DLBCL）是主要的生发中心来源的 DLBCL 亚型，其特征为慢性激活的 B 细胞受体（BCR）信号和 NF-κB 激活，少数病例存在 BCR 信号级联的激活突变，可对此加以解释。我们证明，类似于其在慢性淋巴细胞白血病（CLL）中的重要发病机制作用，自主 BCR 信号可以解释 ABC-DLBCL 中的慢性激活的 BCR 信号。在未经抗原刺激或外部 BCR 交联的情况下，我们测试的 18 种源自 DLBCL 的 BCR 中的 13 种，包括为 IgM 表达而选择的 12 种案例，可诱导小鼠三基因敲除前 B 细胞中自发的钙离子流和 BCR 信号级联的磷酸化。自主 BCR 信号与 IgM 同型相关，依赖于体细胞 BCR 突变和个体 HCDR3 序列，且主要局限于非生发中心 B 细胞来源的 DLBCL。自主 BCR 信号代表源自个体 BCR 序列的 DLBCL 中的一种新的免疫致癌驱动机制，为目前提出的基于遗传学和转录组学的 DLBCL 分类增加了一个新的维度。
