Slomp Anne, Peperzak Victor
Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.
Front Oncol. 2018 Nov 20;8:533. doi: 10.3389/fonc.2018.00533. eCollection 2018.
Apoptosis plays a key role in protection against genomic instability and maintaining tissue homeostasis, and also shapes humoral immune responses. During generation of an antibody response, multiple rounds of B-cell expansion and selection take place in germinal centers (GC) before high antigen affinity memory B-cells and long-lived plasma cells (PC) are produced. These processes are tightly regulated by the intrinsic apoptosis pathway, and malignant transformation throughout and following the GC reaction is often characterized by apoptosis resistance. Expression of pro-survival BCL-2 family protein MCL-1 is essential for survival of malignant PC in multiple myeloma (MM). In addition, BCL-2 and BCL-XL contribute to apoptosis resistance. MCL-1, BCL-2, and BCL-XL expression is induced and maintained by signals from the bone marrow microenvironment, but overexpression can also result from genetic lesions. Since MM PC depend on these proteins for survival, inhibiting pro-survival BCL-2 proteins using novel and highly specific BH3-mimetic inhibitors is a promising strategy for treatment. This review addresses the role and regulation of pro-survival BCL-2 family proteins during healthy PC differentiation and in MM, as well as their potential as therapeutic targets.
细胞凋亡在防止基因组不稳定和维持组织稳态方面发挥着关键作用，同时也塑造体液免疫反应。在抗体反应产生过程中，生发中心（GC）会发生多轮B细胞扩增和选择，然后才产生高抗原亲和力记忆B细胞和长寿浆细胞（PC）。这些过程受到内源性凋亡途径的严格调控，而贯穿GC反应及之后的恶性转化通常以抗凋亡为特征。促生存BCL-2家族蛋白MCL-1的表达对于多发性骨髓瘤（MM）中恶性PC的存活至关重要。此外，BCL-2和BCL-XL也有助于抗凋亡。MCL-1、BCL-2和BCL-XL的表达由骨髓微环境中的信号诱导并维持，但过表达也可能由基因损伤导致。由于MM PC依赖这些蛋白存活，使用新型且高度特异性的BH3模拟抑制剂抑制促生存BCL-2蛋白是一种有前景的治疗策略。本综述探讨了促生存BCL-2家族蛋白在健康PC分化和MM中的作用及调控，以及它们作为治疗靶点的潜力。
