Role of AID in tumorigenesis.
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.
Okazaki
Il-mi
IM
Department of Immunology and Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Kotani
Ai
A
Honjo
Tasuku
T
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D003564:Cytidine Deaminase; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000235:genetics; D016393:Lymphoma, B-Cell / Q000201:enzymology* / Q000235:genetics*; D000090063:Proto-Oncogene Mas; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics; D014178:Translocation, Genetic; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase