BCL6 is critical for the development of a diverse primary B cell repertoire.
BCL6 is critical for the development of a diverse primary B cell repertoire.
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DOI：
10.1084/jem.20091299
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发表时间：
2010-06-07
期刊：
影响因子：
--
通讯作者：
Müschen M
中科院分区：
文献类型：
--
作者：
Duy C;Yu JJ;Nahar R;Swaminathan S;Kweon SM;Polo JM;Valls E;Klemm L;Shojaee S;Cerchietti L;Schuh W;Jäck HM;Hurtz C;Ramezani-Rad P;Herzog S;Jumaa H;Koeffler HP;de Alborán IM;Melnick AM;Ye BH;Müschen M
BCL6保护生发中心（GC） B细胞在体细胞超突变和类别转换重组过程中免受DNA损伤诱导的凋亡。尽管在早期依赖il -7的B细胞前体中未发现BCL6的表达，但我们报道IL-7Rα-Stat5信号通路负调控BCL6。然而，在VH-DJH基因重排和μ重链表达后，b细胞前受体信号通路的激活强烈诱导BCL6的表达，而IL-7Rα-Stat5信号通路被减弱。在B细胞发育从依赖il -7到不依赖il -7的过渡阶段，BCL6被激活，达到与GC B细胞相似的表达水平，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，在Ig轻链基因重排过程中DNA断裂导致Arf和p53过度上调。结果，新骨髓未成熟B细胞池的大小和克隆多样性显著减少。我们得出结论，BCL6对Arf的负调控是B前细胞自我更新和多种多克隆B细胞库形成所必需的。
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-7Rα–Stat5 signaling negatively regulates BCL6. Upon productive VH-DJH gene rearrangement and expression of a μ heavy chain, however, activation of pre–B cell receptor signaling strongly induces BCL6 expression, whereas IL-7Rα–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.
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