TNFAIP3(A20) is a tumor suppressor gene in Hodgkin lymphoma and primary mediastinal B cell lymphoma

Abstract

Proliferation and survival of Hodgkin and Reed/Sternberg (HRS) cells, the malignant cells of classical Hodgkin lymphoma (cHL), are dependent on constitutive activation of nuclearfactor B (NF-B). NF-B activation through various stimuli is negatively regulated by the zinc finger protein A20. To determine whether A20 contributes to the pathogenesis of cHL, we sequenced TNFAIP3, encoding A20, in HL cell lines and laser-microdissected HRS cells from cHL biopsies. We detected somatic mutations in 16 out of 36 cHLs (44%), including missense mutations in 2 out of 16 Epstein-Barr virus-positive (EBV + ) cHLs and a missense mutation, nonsense mutations, and frameshift-causing insertions or deletions in 14 out of 20 EBV  cHLs. In most mutated cases, both TNFAIP3 alleles were inactivated, including frequent chromosomal deletions of TNFAIP3. Reconstitution of wild-type TNFAIP3 in A20deficient cHL cell lines revealed a significant decrease in transcripts of selected NF-B target genes and caused cytotoxicity. Extending the mutation analysis to primary mediastinal B cell lymphoma (PMBL), another lymphoma with constitutive NF-B activity, revealed destructive mutations in 5 out of 14 PMBLs (36%). This report identifies TNFAIP3 (A20), a key regulator of NF-B activity, as a novel tumor suppressor gene in cHL and PMBL. The significantly higher frequency of TNFAIP3 mutations in EBV  than EBV + cHL suggests complementing functions of TNFAIP3 inactivation and EBV infection in cHL pathogenesis.

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.…”

A20 takes on tumors: tumor suppression by an ubiquitin-editing enzyme

“…Considered from another perspective, the severe pathogenetic consequences of A20 deficiency may mean that deletional germline mutations of A20 are unlikely to be detected in the human population. These studies along with the results presented by Schmitz et al (4) and others (5,6) suggest that A20 may be a prevalent suppressor of both autoimmune disease and lymphoma in human patients, thereby providing a critical molecular link between chronic inflammation and cancer.…”

“…Most of the TNFAIP3 mutations found in Hodgkin and mediastinal lymphomas were nonsense or frameshift mutations that prevented production of full-length A20 protein (4). Combined with the observation that both alleles were mutated in the tumor samples, the common pathogenetic mechanism of A20 in lymphoma development is likely a loss of protein function.…”

“…Genetic analyses have identified deletions in chromosome 6q that are associated with Hodgkin lymphoma and other subtypes of B cell lymphomas (e.g., marginal zone lymphomas, MALT lymphomas, and diffuse large B cell lymphomas). As the TNFAIP3 gene is located at 6q23, Schmitz et al (4) proposed that A20 might be pathogenetic in these human cancers. The authors focused their molecular analysis on primary mediastinal B cell lymphomas (PMBLs) and classical Hodgkin lymphoma (cHL), as the transcriptional profiles of these tumors are similar.…”

“…Mutations in NF-B and JAK/STAT signaling proteins cause defects in B cell survival and proliferation and contribute to lymphomagenesis (3). On page 981 of this issue, Schmitz et al examine whether mutations in the TNFAIP3 gene contribute to cellular transformation in human B cell lymphomas (4). Their data show that a large number of Hodgkin lymphomas and primary mediastinal lymphomas contain bi-allelic mutations of TNFAIP3 that result in loss of the A20 protein.…”