Pasqualucci Laura, Bhagat Govind, Jankovic Mila, Compagno Mara, Smith Paula, Muramatsu Masamichi, Honjo Tasuku, Morse Herbert C, Nussenzweig Michel C, Dalla-Favera Riccardo
Institute for Cancer Genetics, the Departments of Pathology and Genetics & Development, and the Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York 10032, USA.
Nat Genet. 2008 Jan;40(1):108-12. doi: 10.1038/ng.2007.35. Epub 2007 Dec 9.
Most human B cell non-Hodgkin's lymphomas (B-NHLs) derive from germinal centers (GCs), the structure in which B cells undergo somatic hypermutation (SHM) and class switch recombination (CSR) before being selected for high-affinity antibody production. The pathogenesis of B-NHL is associated with distinct genetic lesions, including chromosomal translocations and aberrant SHM, which arise from mistakes occurring during CSR and SHM. A direct link between these DNA remodeling events and GC lymphoma development, however, has not been demonstrated. Here we have crossed three mouse models of B cell lymphoma driven by oncogenes (Myc, Bcl6 and Myc/Bcl6; refs. 5,6) with mice lacking activation-induced cytidine deaminase (AID), the enzyme required for both CSR and SHM. We show that AID deficiency prevents Bcl6-dependent, GC-derived B-NHL, but has no impact on Myc-driven, pre-GC lymphomas. Accordingly, abrogation of AID is associated with the disappearance of CSR- and SHM-mediated structural alterations. These results show that AID is required for GC-derived lymphomagenesis, supporting the notion that errors in AID-mediated antigen-receptor gene modification processes are principal contributors to the pathogenesis of human B-NHL.
大多数人类B细胞非霍奇金淋巴瘤（B-NHL）起源于生发中心（GC），在该结构中，B细胞在被选择用于产生高亲和力抗体之前会经历体细胞超突变（SHM）和类别转换重组（CSR）。B-NHL的发病机制与不同的基因损伤有关，包括染色体易位和异常的SHM，这些损伤源于CSR和SHM过程中发生的错误。然而，这些DNA重塑事件与GC淋巴瘤发展之间的直接联系尚未得到证实。在这里，我们将三种由致癌基因驱动的B细胞淋巴瘤小鼠模型（Myc、Bcl6和Myc/Bcl6；参考文献5、6）与缺乏激活诱导的胞苷脱氨酶（AID）的小鼠进行杂交，AID是CSR和SHM所必需的酶。我们发现，AID缺陷可预防依赖Bcl6的、源自GC的B-NHL，但对Myc驱动的GC前淋巴瘤没有影响。因此，AID的缺失与CSR和SHM介导的结构改变的消失有关。这些结果表明，AID是源自GC的淋巴瘤发生所必需的，支持了AID介导的抗原受体基因修饰过程中的错误是人类B-NHL发病机制的主要促成因素这一观点。
