The role of A20 in the pathogenesis of lymphocytic malignancy

Autoimmune phenomena were identified in many different cases of hematological diseases and solid tumors in which abnormal A20 expression was characterized. Recently, a number of studies have shown that A20 deletions and mutations are frequently found in lymphomas, suggesting that it may be involved in pathogenesis [1].A20 is also known as tumor necrosis factor-α (TNFα)-induced protein 3 (TNFAIP3), which was first discovered in 1990 by Dixit and colleagues as a cytokine-induced gene in human umbilical vein endothelial cells [2,3]. This protein was originally identified as a key regulator of inflammation signaling pathways and a negative regulator of the nuclear factor kappa B (NF-κB) activation pathway, which could attenuate the NF-κB activity triggered by signaling from several surface receptors including tumor necrosis factors receptor (TNFR), Toll-like receptor (TLR), and B cell receptor (BCR) [4].The A20 gene is located on chromosome 6q23.3, and the cDNA sequence is 4,440 bp long with an open reading frame of 2,370 nucleotides that encodes a protein predicted to contain 790 amino acids. A20 contains seven zinc finger (ZnF) domains in its C-terminus including one that functions as an E3 ligase, while an OUT (ovarian tumor) domain is embedded in its N-terminus [2,3,5-9]. Structural studies have revealed that the fourth zinc finger (ZnF4) interacts with mono-ubiquitins and K63-linked polyubiquitin chains [9].A20 expression may be induced in multiple organs by various stimuli including interleukin-1β(IL-1β), TNF-α, and Epstein-Barr virus (EBV) - latent membrane protein1(LMP1). Although A20 is inducible by proinflammatory cytokines in most cell types, the regulation of A20 differs in lymphocytes. Temporally restricted and tissue-specific A20 expression patterns were observed with strikingly high levels in lymphoid organs including the thymus, spleen, and gut-associated lymphoid tissue. A20 is constitutively expressed in immature and mature thymocyte subpopulations and