Xavier Serene, Nguyen Vivian, Khairnar Vishal, Phan An, Yang Lu, Nelson Michael S, Shukla Ravi P, Wang Jinhui, Li Aimin, Geng Huimin, Lee Jaewoong, Sadras Teresa, Pham Lan V, Weisenburger Dennis D, Chan Wing C, Lang Karl S, Shouse Geoffrey P, Danilov Alexey V, Song Joo Y, Parekh Samir, Müschen Markus, Ngo Vu N
Department of Systems Biology, City of Hope Comprehensive Cancer Center, Monrovia, CA, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Nat Commun. 2025 May 29;16(1):4967. doi: 10.1038/s41467-025-60208-3.
B-cell receptor (BCR) signaling plays an important role in the pathogenesis of mantle cell lymphoma (MCL), but the detailed mechanisms are not fully understood. In this study, through a genome-wide loss-of-function screen, we identify carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) as an essential factor in a subset of MCL tumors. Our signal transduction studies reveal that CEACAM1 plays a critical role in BCR activation through involvement in two dynamic processes. First, following BCR engagement, CEACAM1 co-localizes to the membrane microdomains (lipid rafts) by anchoring to the F-actin cytoskeleton through the adaptor protein filamin A. Second, CEACAM1 recruits and increases the abundance of SYK in the BCR complex leading to BCR activation. These activities of CEACAM1 require its cytoplasmic tail and the N-terminal ectodomain. Considering that previous studies have extensively characterized CEACAM1 as an ITIM-bearing inhibitory receptor, our findings regarding its activating role are both surprising and context-dependent, which may have implications for BCR-targeting therapies.
B细胞受体（BCR）信号传导在套细胞淋巴瘤（MCL）的发病机制中起重要作用，但其详细机制尚未完全明确。在本研究中，通过全基因组功能丧失筛选，我们鉴定出癌胚抗原相关细胞粘附分子1（CEACAM1）是一部分MCL肿瘤中的关键因子。我们的信号转导研究表明，CEACAM1通过参与两个动态过程在BCR激活中起关键作用。首先，在BCR结合后，CEACAM1通过衔接蛋白细丝蛋白A锚定到F-肌动蛋白细胞骨架，从而共定位于膜微区（脂筏）。其次，CEACAM1招募并增加BCR复合物中SYK的丰度，导致BCR激活。CEACAM1的这些活性需要其胞质尾和N端胞外结构域。鉴于先前的研究已广泛将CEACAM1表征为带有免疫受体酪氨酸抑制基序（ITIM）的抑制性受体，我们关于其激活作用的发现既令人惊讶又依赖于背景，这可能对BCR靶向治疗有影响。
