Croce Carlo M, Vaux David, Strasser Andreas, Opferman Joseph T, Czabotar Peter E, Fesik Stephen W
Department of Cancer Biology and Genetics and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
The Walter and Eliza Hall Institute, Parkville, VIC, Australia.
Cell Death Differ. 2025 Apr 9. doi: 10.1038/s41418-025-01481-z.
The landmark discovery of the BCL-2 gene and then its function marked the identification of inhibition of apoptotic cell death as a crucial novel mechanism driving cancer development and launched the quest to discover the molecular control of apoptosis. This work culminated in the generation of specific inhibitors that are now in clinical use, saving and improving tens of thousands of lives annually. Here, some of the original players of this story, describe the sequence of critical discoveries. The t(14;18) chromosomal translocation, frequently observed in follicular lymphoma, allowed the identification and the cloning of a novel oncogene (BCL-2) juxtaposed to the immunoglobulin heavy chain gene locus (IgH). Of note, BCL-2 acted in a distinct manner as compared to then already known oncogenic proteins like ABL and c-MYC. BCL-2 did not promote cell proliferation but inhibited cell death, as originally shown in growth factor dependent haematopoietic progenitor cell lines (e.g., FDC-P1) and in Eμ-Myc/Eμ-Bcl-2 double transgenic mice. Following a rapid expansion of the BCL-2 protein family, the Abbott Laboratories solved the first structure of BCL-XL and subsequently the BCL-XL/BAK peptide complex, opening the way to understanding the structures of other BCL-2 family members and, finally, to the generation of inhibitors of the different pro-survival BCL-2 proteins, thanks to the efforts of Servier/Norvartis, Genentech/WEHI, AbbVie, Amgen, Prelude and Gilead. Although the BCL-2 inhibitor Venetoclax is in clinical use and inhibitors of BCL-XL and MCL-1 are undergoing clinical trials, several questions remain on whether therapeutic windows can be achieved and what other agents should be used in combination with BH3 mimetics to achieve optimal therapeutic impact for cancer therapy. Finally, the control of the expression of BH3-only proteins and pro-survival BCL-2 family members needs to be better understood as this may identify novel targets for cancer therapy. This story is still not concluded!
BCL-2基因的里程碑式发现及其功能，标志着凋亡细胞死亡抑制作为驱动癌症发展的关键新机制被确定，并开启了探索细胞凋亡分子调控的征程。这项工作最终催生了目前正在临床使用的特异性抑制剂，每年挽救并改善了数万人的生命。在此，这个故事的一些最初参与者描述了关键发现的先后顺序。在滤泡性淋巴瘤中经常观察到的t(14;18)染色体易位，使得与免疫球蛋白重链基因座（IgH）并列的一种新型癌基因（BCL-2）得以鉴定和克隆。值得注意的是，与当时已知的致癌蛋白如ABL和c-MYC相比，BCL-2的作用方式截然不同。BCL-2并不促进细胞增殖，而是抑制细胞死亡，这最初在依赖生长因子的造血祖细胞系（如FDC-P1）和Eμ-Myc/Eμ-Bcl-2双转基因小鼠中得到证实。随着BCL-2蛋白家族的迅速扩张，雅培实验室解析了BCL-XL的首个结构，随后又解析了BCL-XL/BAK肽复合物的结构，这为理解其他BCL-2家族成员的结构，最终为生成不同促生存BCL-2蛋白的抑制剂开辟了道路，这要归功于施维雅/诺华、基因泰克/沃尔特与伊丽莎·霍尔医学研究所、艾伯维、安进、普瑞路德和吉利德的努力。尽管BCL-2抑制剂维奈托克已在临床使用，BCL-XL和MCL-1的抑制剂正在进行临床试验，但关于是否能实现治疗窗口以及与BH3模拟物联合使用何种其他药物以实现癌症治疗的最佳疗效，仍有几个问题有待解决。最后，对仅含BH3结构域蛋白和促生存BCL-2家族成员表达的调控需要更好地理解，因为这可能会确定癌症治疗的新靶点。这个故事仍未结束！
