Role of AID in tumorigenesis.
Role of AID in tumorigenesis.
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DOI：
10.1016/s0065-2776(06)94008-5
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发表时间：
2007-01-01
影响因子：
--
通讯作者：
Honjo, Tasuku
中科院分区：
文献类型：
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作者：
Okazaki, Il-mi;Kotani, Ai;Honjo, Tasuku
成熟B细胞淋巴瘤的标志是涉及IG基因座和原癌基因的相互染色体易位，其通常导致易位基因的失调的组成型表达。除了这样的易位，原癌基因经常高度突变的生发中心（GC）衍生的B细胞淋巴瘤。虽然长期以来一直怀疑异常的、错误的类别转换重组（CSR）和体细胞超突变（SHM）事件引起染色体易位和癌基因突变，并且因此在大多数B细胞淋巴瘤的发病机制中起关键作用，但是CSR和SHM的这种失调的分子基础仅开始通过最近的遗传学方法来阐明。激活诱导的胞苷脱氨酶（AID）是启动CSR和SHM的关键酶，在AID转基因小鼠的研究中揭示了其致瘤能力。此外，艾滋病缺陷小鼠的实验清楚地表明，艾滋病不仅是必要的c-myc/IgH易位，但也为恶性进展的易位轴承淋巴瘤前体细胞，可能是通过引入额外的遗传命中。通常，AID表达仅在GC中的活化B细胞中瞬时和特异性诱导。然而，最近的研究表明，AID可以直接在GC外的B细胞中被各种病原体诱导，包括与人类恶性肿瘤相关的转化病毒。事实上，AID表达并不局限于GC衍生的B细胞淋巴瘤，但也发现在其他类型的B细胞淋巴瘤，甚至在非淋巴肿瘤，表明异位表达的AID参与肿瘤的发生和疾病的进展，在各种各样的细胞类型。
A hallmark of mature B-cell lymphomas is reciprocal chromosomal translocations involving the Ig locus and a proto-oncogene, which usually result in the deregulated, constitutive expression of the translocated gene. In addition to such translocations, proto-oncogenes are frequently hypermutated in germinal center (GC)-derived B-cell lymphomas. Although aberrant, mistargeted class switch recombination (CSR) and somatic hypermutation (SHM) events have long been suspected of causing chromosomal translocations and mutations in oncogenes, and thus of playing a critical role in the pathogenesis of most B-cell lymphomas, the molecular basis for such deregulation of CSR and SHM is only beginning to be elucidated by recent genetic approaches. The tumorigenic ability of activation-induced cytidine deaminase (AID), a key enzyme that initiates CSR and SHM, was revealed in studies on AID transgenic mice. In addition, experiments with AID-deficient mice clearly showed that AID is required not only for the c-myc/IgH translocation but also for the malignant progression of translocation-bearing lymphoma precursor cells, probably by introducing additional genetic hits. Normally, AID expression is only transiently and specifically induced in activated B cells in GCs. However, recent studies indicate that AID can be induced directly in B cells outside the GCs by various pathogens, including transforming viruses associated with human malignancies. Indeed, AID expression is not restricted to GC-derived B-cell lymphomas, but is also found in other types of B-cell lymphoma and even in nonlymphoid tumors, suggesting that ectopically expressed AID is involved in tumorigenesis and disease progression in a wide variety of cell types.