Ye B H, Cattoretti G, Shen Q, Zhang J, Hawe N, de Waard R, Leung C, Nouri-Shirazi M, Orazi A, Chaganti R S, Rothman P, Stall A M, Pandolfi P P, Dalla-Favera R
Department of Pathology, Columbia University, New York, New York 10032, USA.
Nat Genet. 1997 Jun;16(2):161-70. doi: 10.1038/ng0697-161.
Structural alterations of the promoter region of the BCL-6 proto-oncogene represent the most frequent genetic alteration associated with non-Hodgkin lymphoma, a malignancy often deriving from germinal-centre B cells. The BCL-6 gene encodes a zinc-finger transcriptional repressor normally expressed in both B cells and CD4+ T cells within germinal centres, but its precise function is unknown. We show that mice deficient in BCL-6 displayed normal B-cell, T-cell and lymphoid-organ development but have a selective defect in T-cell-dependent antibody responses. This defect included a complete lack of affinity maturation and was due to the inability of follicular B cells to proliferate and form germinal centres. In addition, BCL-6-deficient mice developed an inflammatory response in multiple organs characterized by infiltrations of eosinophils and IgE-bearing B lymphocytes typical of a Th2-mediated hyperimmune response. Thus, BCL-6 functions as a transcriptional switch that controls germinal centre formation and may also modulate specific T-cell-mediated responses. Altered expression of BCL-6 in lymphoma represents a deregulation of the pathway normally leading to B cell proliferation and germinal centre formation.
BCL-6原癌基因启动子区域的结构改变是与非霍奇金淋巴瘤相关的最常见基因改变，非霍奇金淋巴瘤是一种通常起源于生发中心B细胞的恶性肿瘤。BCL-6基因编码一种锌指转录抑制因子，通常在生发中心的B细胞和CD4+T细胞中表达，但其确切功能尚不清楚。我们发现，缺乏BCL-6的小鼠B细胞、T细胞和淋巴器官发育正常，但在T细胞依赖性抗体反应中存在选择性缺陷。这种缺陷包括完全缺乏亲和力成熟，原因是滤泡B细胞无法增殖并形成生发中心。此外，缺乏BCL-6的小鼠在多个器官中出现炎症反应，其特征是嗜酸性粒细胞和携带IgE的B淋巴细胞浸润，这是Th2介导的超敏反应的典型表现。因此，BCL-6作为一种转录开关，控制生发中心的形成，也可能调节特定的T细胞介导的反应。淋巴瘤中BCL-6表达的改变代表了通常导致B细胞增殖和生发中心形成的途径的失调。
