TNFAIP3/A20 functions as a novel tumor suppressor gene in several subtypes of non-Hodgkin lymphomas

Abstract

The constitutive activation of nuclear factor-B (NF-B) has been implicated in tumorigenesis of lymphoid malignancies. We have previously shown that chromosome 6q was frequently deleted in ocular marginal zone B-cell lymphoma and identified TNFAIP3/A20, a negative regulator of NF-B pathways, as the primary target for 6q deletion. In the study reported here, we extended the analysis to other subsets of non-Hodgkin lymphomas and found that A20 is frequently deleted in mantle cell lymphoma and diffuse large B-cell lymphoma. Importantly, A20 promoter methylation or gene mutation is also frequently detected in these lymphomas, raising the possibility that inactivation of A20 may be involved in lymphomagenesis. To address this question, we conducted overexpression experiments in lymphoma cell lines with A20 deletion and down-regulated expression of A20 with an siRNA technique in EpsteinBarr virus-infected lymphoblastoid cell lines. These experiments found that overexpression of A20 induced apoptosis and silencing of A20 was associated with resistance to apoptosis and enhanced clonogenicity. The cells with down-regulated A20 exhibited enhanced NF-B activities, which may account for the observed effects. These results indicate that our study provides a novel insight into molecular mechanisms leading to lymphoma and that specific targeting of NF-B pathways may be advantageous for treatment.

BCR and TLR signaling pathways are recurrently targeted by genetic changes in splenic marginal zone lymphomas

“…[1][2][3][4][5][6][7] In addition to A20, several NF-kB positive regulators, including CARD11, MYD88 and CD79 are frequently activated by mutation in ABC-DLBCL. [8][9][10] Our recent study also showed frequent inactivation of ABIN1, a critical adaptor molecule of the A20 inhibitory complex, in gastrointestinal DLBCL.…”

Deubiquitinases in cancer: new functions and therapeutic options

“…The generation of mutant mice deficient in CYLD has confirmed the tumor-suppressor role of this DUB because of its ability to enhance NK-kB activity (Zhang et al, 2006b). In the case of A20, chromosomal deletions and inactivating mutations have been found in several lymphoma subtypes (Honma et al, 2009;Novak et al, 2009), whereas point mutations and deletions in BAP1 have been described in breast and lung cancer (Jensen et al, 1998;Harbour et al, 2010). Furthermore, BAP1-inactivating mutations have been identified in 84% of metastasizing uveal melanomas (Harbour et al, 2010) and in 23% of malignant pleural mesotheliomas (Bott et al, 2011).…”

“…This could be the case of UCHL1, in which silencing by promoter methylation has been observed in some cancer cell lines and primary tumors (Yu et al, 2008). Moreover, A20 is also inactivated by promoter methylation in several lymphomas (Honma et al, 2009). Another interesting approach in this regard is the use of exogenous compounds with the ability to compensate the loss of function of tumor-suppressor DUBs inactivated in cancer.…”

Whole genome profiling and other high throughput technologies in lymphoid neoplasms—current contributions and future hopes

“…14,27 The inhibitor of NFkB TNFAIP3/A20 was initially identified as the target of the 6q23 deletions found in ocular MZL by array-CGH. 28 Inactivating mutations of this gene were subsequently found in other lymphomas carrying 6q23 deletions including ABC-DLBCL, MCL, and Hodgkin's lymphoma (HL). 28,29 Inactivating mutations of PRDM1/BLIMP1 occur in DLBCL with deletions of 6q21.…”

“…28 Inactivating mutations of this gene were subsequently found in other lymphomas carrying 6q23 deletions including ABC-DLBCL, MCL, and Hodgkin's lymphoma (HL). 28,29 Inactivating mutations of PRDM1/BLIMP1 occur in DLBCL with deletions of 6q21. A recent combined CGH array and gene expression profiling study of NK-cell neoplasms has also recognized 6q21 deletions and inactivating PRDM1 mutations in these tumors.…”