Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy.
Immunol Rev. 2019 Mar;288(1):178-197. doi: 10.1111/imr.12734.
The rearrangement of immunoglobulin loci during the germinal center reaction is associated with an increased risk of chromosomal translocations that activate oncogenes such as MYC, BCL2 or BCL6, thus contributing to the development of B-cell lymphomas. MYC and BCL2 activation are initiating events in Burkitt's (BL) and Follicular Lymphoma (FL), respectively, but can occur at later stages in other subtypes such as Diffuse Large-B Cell Lymphoma (DLBCL). MYC can also be activated during the progression of FL to the transformed stage. Thus, either DLBCL or FL can give rise to aggressive double-hit lymphomas (DHL) with concurrent activation of MYC and BCL2. Research over the last three decades has improved our understanding of the functions of these oncogenes and the basis for their cooperative action in lymphomagenesis. MYC, in particular, is a transcription factor that contributes to cell activation, growth and proliferation, while concomitantly sensitizing cells to apoptosis, the latter being blocked by BCL2. Here, we review our current knowledge about the role of MYC in germinal center B-cells and lymphomas, discuss MYC-induced dependencies that can sensitize cancer cells to select pharmacological inhibitors, and illustrate their therapeutic potential in aggressive lymphomas-and in particular in DHL, in combination with BCL2 inhibitors.
免疫球蛋白基因座在生发中心反应期间的重排与染色体易位的风险增加有关，这些易位会激活癌基因，如 MYC、BCL2 或 BCL6，从而促进 B 细胞淋巴瘤的发展。MYC 和 BCL2 的激活分别是伯基特淋巴瘤（BL）和滤泡性淋巴瘤（FL）的起始事件，但也可能在其他亚型（如弥漫性大 B 细胞淋巴瘤（DLBCL））的后期发生。在 FL 向转化阶段的进展过程中，MYC 也可以被激活。因此，无论是 DLBCL 还是 FL，都可能导致同时激活 MYC 和 BCL2 的侵袭性双打击淋巴瘤（DHL）。过去三十年来的研究提高了我们对这些癌基因功能及其在淋巴瘤发生中的协同作用基础的理解。特别是 MYC 是一种转录因子，有助于细胞激活、生长和增殖，同时使细胞对凋亡敏感，而 BCL2 则阻止了凋亡。在这里，我们回顾了我们目前对 MYC 在生发中心 B 细胞和淋巴瘤中的作用的认识，讨论了 MYC 诱导的依赖性，这些依赖性可以使癌细胞对选择药理学抑制剂敏感，并说明了它们在侵袭性淋巴瘤中的治疗潜力，特别是在 DHL 中，与 BCL2 抑制剂联合使用。
