Department of Microbiology and Oncology, University of the Ryukyus, Nishihara, Okinawa, Japan.
Carcinogenesis. 2011 Jan;32(1):110-9. doi: 10.1093/carcin/bgq222. Epub 2010 Oct 25.
Adult T-cell leukemia (ATL) is a T-cell malignancy associated with human T-cell leukemia virus type 1 (HTLV-1). Mutations of tumor suppressor genes have been described in ATL. Although Tax, a product of HTLV-1, is associated with cellular genetic aberrations, the mechanisms of such association are not fully clear. Activation-induced cytidine deaminase (AID) is involved in somatic DNA alterations of the immunoglobulin gene for amplification of immune diversity. However, inappropriate expression of AID acts as a genomic mutator that contributes to tumorigenesis. To gain insight into the molecular mechanism underlying the emergence of somatic mutations in various genes during leukemogenesis, we examined the expression of AID. HTLV-1-infected T-cell lines and ATL cells expressed high levels of AID compared with uninfected T-cell lines and normal peripheral blood mononuclear cells (PBMCs). Immunohistochemistry showed AID-positive ATL cells in lymph nodes and skin lesions. Infection of a human T-cell line and normal PBMCs with HTLV-1 induced AID expression. Tax transcriptionally activated AID gene through both the nuclear factor-kappaB subunit p50 and cyclic adenosine 3',5'-monophosphate response element-binding protein signaling pathways. p50, which lacks a transactivation domain, interacted with the transcriptional coactivator Bcl-3 in HTLV-1-infected T cells. Thus, activation of p50/Bcl-3 complexes in T cells in response to Tax might explain the constitutive expression of AID in HTLV-1-infected T cells. The constitutive expression of AID in ATL cells can be speculated to result from mutations induced by the Tax-activated AID and/or other Tax-associated mutagenic mechanisms during the pre-leukemic stage, which cause functional modification within the AID promoter or in any of its cellular regulatory activator proteins.
成人 T 细胞白血病（ATL）是一种与人类 T 细胞白血病病毒 1（HTLV-1）相关的 T 细胞恶性肿瘤。在 ATL 中已经描述了肿瘤抑制基因的突变。尽管 HTLV-1 的产物 Tax 与细胞遗传异常有关，但这种关联的机制尚不完全清楚。激活诱导的胞嘧啶脱氨酶（AID）参与免疫球蛋白基因的体细胞 DNA 改变，以扩增免疫多样性。然而，AID 的不当表达作为基因组诱变剂，有助于肿瘤发生。为了深入了解白血病发生过程中各种基因体细胞突变出现的分子机制，我们检查了 AID 的表达。与未感染的 T 细胞系和正常外周血单核细胞（PBMC）相比，HTLV-1 感染的 T 细胞系和 ATL 细胞表达高水平的 AID。免疫组化显示淋巴结和皮肤病变中的 AID 阳性 ATL 细胞。HTLV-1 感染人 T 细胞系和正常 PBMC 诱导 AID 表达。Tax 通过核因子-kappaB 亚单位 p50 和环磷酸腺苷 3'，5'-单磷酸反应元件结合蛋白信号通路转录激活 AID 基因。缺乏转录激活域的 p50 与 HTLV-1 感染的 T 细胞中的转录共激活子 Bcl-3 相互作用。因此，Tax 对 T 细胞中 p50/Bcl-3 复合物的激活可能解释了 HTLV-1 感染的 T 细胞中 AID 的组成性表达。ATL 细胞中 AID 的组成性表达可以推测是由于 Tax 激活的 AID 诱导的突变和/或在白血病前阶段的其他 Tax 相关诱变机制引起的，这些突变导致 AID 启动子或其任何细胞调节激活蛋白内的功能修饰。
