Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University, London, UK.
Department of Internal Medicine III, University of Ulm, Ulm, Germany.
Leukemia. 2018 Feb;32(2):364-375. doi: 10.1038/leu.2017.255. Epub 2017 Aug 14.
Somatic hypermutation (SHM) is a pivotal process in adaptive immunity that occurs in the germinal centre and allows B cells to change their primary DNA sequence and diversify their antigen receptors. Here, we report that genome binding of Lamin B1, a component of the nuclear envelope involved in epigenetic chromatin regulation, is reduced during B-cell activation and formation of lymphoid germinal centres. Chromatin immunoprecipitation-Seq analysis showed that kappa and heavy variable immunoglobulin domains were released from the Lamin B1 suppressive environment when SHM was induced in B cells. RNA interference-mediated reduction of Lamin B1 resulted in spontaneous SHM as well as kappa-light chain aberrant surface expression. Finally, Lamin B1 expression level correlated with progression-free and overall survival in chronic lymphocytic leukaemia, and was strongly involved in the transformation of follicular lymphoma. In summary, here we report that Lamin B1 is a negative epigenetic regulator of SHM in normal B-cells and a 'mutational gatekeeper', suppressing the aberrant mutations that drive lymphoid malignancy.
体细胞超突变（SHM）是适应性免疫中的一个关键过程，发生在生发中心，使 B 细胞能够改变其主要 DNA 序列并多样化其抗原受体。在这里，我们报告说，核膜的组成部分 Lamin B1 的基因组结合在 B 细胞激活和形成淋巴生发中心期间减少。染色质免疫沉淀-Seq 分析表明，当 B 细胞中诱导 SHM 时，κ 和重可变免疫球蛋白结构域从 Lamin B1 的抑制环境中释放出来。RNA 干扰介导的 Lamin B1 减少导致自发 SHM 以及 κ-轻链异常表面表达。最后，Lamin B1 的表达水平与慢性淋巴细胞白血病的无进展生存期和总生存期相关，并且强烈参与滤泡性淋巴瘤的转化。总之，在这里我们报告说，Lamin B1 是正常 B 细胞中 SHM 的负表观遗传调节剂，也是一个“突变守门员”，抑制驱动淋巴恶性肿瘤的异常突变。
