Childrens Hospital Los Angeles and Leukemia and Lymphoma Program, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90027, USA.
J Exp Med. 2010 Jun 7;207(6):1209-21. doi: 10.1084/jem.20091299. Epub 2010 May 24.
BCL6 protects germinal center (GC) B cells against DNA damage-induced apoptosis during somatic hypermutation and class-switch recombination. Although expression of BCL6 was not found in early IL-7-dependent B cell precursors, we report that IL-7Ralpha-Stat5 signaling negatively regulates BCL6. Upon productive VH-DJH gene rearrangement and expression of a mu heavy chain, however, activation of pre-B cell receptor signaling strongly induces BCL6 expression, whereas IL-7Ralpha-Stat5 signaling is attenuated. At the transition from IL-7-dependent to -independent stages of B cell development, BCL6 is activated, reaches expression levels resembling those in GC B cells, and protects pre-B cells from DNA damage-induced apoptosis during immunoglobulin (Ig) light chain gene recombination. In the absence of BCL6, DNA breaks during Ig light chain gene rearrangement lead to excessive up-regulation of Arf and p53. As a consequence, the pool of new bone marrow immature B cells is markedly reduced in size and clonal diversity. We conclude that negative regulation of Arf by BCL6 is required for pre-B cell self-renewal and the formation of a diverse polyclonal B cell repertoire.
BCL6 可保护生发中心 (GC) B 细胞免受体细胞超突变和类别转换重组过程中 DNA 损伤诱导的细胞凋亡。虽然在早期依赖 IL-7 的 B 细胞前体中未发现 BCL6 的表达，但我们报告称，IL-7Ralpha-Stat5 信号通路可负向调节 BCL6。然而，当发生有效 VH-DJH 基因重排并表达 μ 重链时，前 B 细胞受体信号的激活会强烈诱导 BCL6 的表达，而 IL-7Ralpha-Stat5 信号则会减弱。在 B 细胞发育从依赖 IL-7 向非依赖 IL-7 的阶段过渡时，BCL6 被激活，表达水平类似于 GC B 细胞中的表达水平，并在免疫球蛋白 (Ig) 轻链基因重组过程中保护前 B 细胞免受 DNA 损伤诱导的凋亡。在缺乏 BCL6 的情况下，Ig 轻链基因重排过程中的 DNA 断裂会导致 Arf 和 p53 的过度上调。结果，新的骨髓不成熟 B 细胞池的大小和克隆多样性明显减少。我们得出结论，BCL6 对 Arf 的负向调节是前 B 细胞自我更新和形成多样化的多克隆 B 细胞库所必需的。
