Hagemann Philipp M, Kenyon Angelique N, Cabrera-Orefice Alfredo, Arp Abbey B, Hesius Eva A M, van den Brand Michiel, van Deventer Sjoerd J, de Jong Daphne, Scheijen Blanca, Xu-Monette Zijun Y, Brandt Ulrich, Spruijt Cornelia G, Vermeulen Michiel, Ter Beest Martin, Young Ken H, van Spriel Annemiek B
Department of Medical BioSciences, Radboud Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, The Netherlands.
Radboud Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, The Netherlands.
Cell Mol Life Sci. 2025 Jun 4;82(1):221. doi: 10.1007/s00018-025-05747-0.
CD151 is a broadly expressed four-transmembrane protein (tetraspanin) that interacts with laminin-binding integrins like integrin alpha 3 (ITGA3). CD151 drives tumor development and expression correlates with poor prognosis in solid cancers, but CD151 has not been studied in B cell malignancies. We investigated CD151 expression on normal human B cells and B cell lymphomas using highly sensitive flow cytometry and immunohistochemistry. Expression of CD151 increased during B cell differentiation from naïve to memory B cells to plasma cells. B lymphoma cell lines and human lymphoma biopsy samples expressed higher levels of CD151 compared to normal B cells, but CD151-deficient lymphomas were identified as well. To investigate the function of CD151 in B cells, CD151-deficient and stably transduced CD151 expressing B lymphoma cell lines were generated. Immunoprecipitation-mass spectrometry analysis of CD151 protein complexes identified integrin beta 2 (ITGB2) as new interaction partner in lymphoma cells. Deficiency of CD151 decreased cell surface expression of alpha integrin subunits L (ITGAL) and M (ITGAM), and impaired ICAM-1-mediated cell spreading. Interestingly, B cells and lymphomas did not express ITGA3-bound CD151 compared to T cells that expressed two different populations of integrin-bound and integrin-free CD151. Despite CD151 expression not being related to clinical outcome of patients with diffuse large B cell lymphoma (DLBCL), CD151 expression was predominantly detected in the activated (ABC) subset of DLBCL. Taken together, we identified a new molecular association of CD151 with ITGB2, and targeting integrin-free CD151 in DLBCL may represent a new target for immunotherapy.
CD151是一种广泛表达的四跨膜蛋白（四跨膜蛋白超家族成员），它与层粘连蛋白结合整合素相互作用，如整合素α3（ITGA3）。CD151促进肿瘤发展，其表达与实体癌的不良预后相关，但尚未在B细胞恶性肿瘤中进行研究。我们使用高灵敏度流式细胞术和免疫组织化学研究了CD151在正常人B细胞和B细胞淋巴瘤上的表达。从幼稚B细胞到记忆B细胞再到浆细胞的B细胞分化过程中，CD151的表达增加。与正常B细胞相比，B淋巴瘤细胞系和人淋巴瘤活检样本表达更高水平的CD151，但也鉴定出了CD151缺陷型淋巴瘤。为了研究CD151在B细胞中的功能，构建了CD151缺陷型和稳定转导表达CD151的B淋巴瘤细胞系。对CD151蛋白复合物进行免疫沉淀-质谱分析，确定整合素β2（ITGB2）是淋巴瘤细胞中的新相互作用伙伴。CD151缺陷会降低α整合素亚基L（ITGAL）和M（ITGAM）的细胞表面表达，并损害细胞间黏附分子-1（ICAM-1）介导的细胞铺展。有趣的是，与表达整合素结合型和非整合素结合型两种不同群体CD151的T细胞相比，B细胞和淋巴瘤不表达ITGA3结合的CD151。尽管CD151的表达与弥漫性大B细胞淋巴瘤（DLBCL）患者的临床结局无关，但CD151表达主要在DLBCL的活化（ABC）亚组中检测到。综上所述，我们确定了CD151与ITGB2的新分子关联，靶向DLBCL中非整合素结合型CD151可能代表免疫治疗的新靶点。
