Frequent inactivation of A20 in B-cell lymphomas.
A20 is a negative regulator of the NF-kappaB pathway and was initially identified as being rapidly induced after tumour-necrosis factor-alpha stimulation. It has a pivotal role in regulation of the immune response and prevents excessive activation of NF-kappaB in response to a variety of external stimuli; recent genetic studies have disclosed putative associations of polymorphic A20 (also called TNFAIP3) alleles with autoimmune disease risk. However, the involvement of A20 in the development of human cancers is unknown. Here we show, using a genome-wide analysis of genetic lesions in 238 B-cell lymphomas, that A20 is a common genetic target in B-lineage lymphomas. A20 is frequently inactivated by somatic mutations and/or deletions in mucosa-associated tissue lymphoma (18 out of 87; 21.8%) and Hodgkin's lymphoma of nodular sclerosis histology (5 out of 15; 33.3%), and, to a lesser extent, in other B-lineage lymphomas. When re-expressed in a lymphoma-derived cell line with no functional A20 alleles, wild-type A20, but not mutant A20, resulted in suppression of cell growth and induction of apoptosis, accompanied by downregulation of NF-kappaB activation. The A20-deficient cells stably generated tumours in immunodeficient mice, whereas the tumorigenicity was effectively suppressed by re-expression of A20. In A20-deficient cells, suppression of both cell growth and NF-kappaB activity due to re-expression of A20 depended, at least partly, on cell-surface-receptor signalling, including the tumour-necrosis factor receptor. Considering the physiological function of A20 in the negative modulation of NF-kappaB activation induced by multiple upstream stimuli, our findings indicate that uncontrolled signalling of NF-kappaB caused by loss of A20 function is involved in the pathogenesis of subsets of B-lineage lymphomas.
Kato
Motohiro
M
Cancer Genomics Project, Department of Pediatrics, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
Sanada
Masashi
M
Kato
Itaru
I
Sato
Yasuharu
Y
Takita
Junko
J
Takeuchi
Kengo
K
Niwa
Akira
A
Chen
Yuyan
Y
Nakazaki
Kumi
K
Nomoto
Junko
J
Asakura
Yoshitaka
Y
Muto
Satsuki
S
Tamura
Azusa
A
Iio
Mitsuru
M
Akatsuka
Yoshiki
Y
Hayashi
Yasuhide
Y
Mori
Hiraku
H
Igarashi
Takashi
T
Kurokawa
Mineo
M
Chiba
Shigeru
S
Mori
Shigeo
S
Ishikawa
Yuichi
Y
Okamoto
Koji
K
Tobinai
Kensei
K
Nakagama
Hitoshi
H
Nakahata
Tatsutoshi
T
Yoshino
Tadashi
T
Kobayashi
Yukio
Y
Ogawa
Seishi
S
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000235:genetics* / Q000378:metabolism*; D004268:DNA-Binding Proteins; D015870:Gene Expression; D020868:Gene Silencing; D016678:Genome / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism*; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000503:physiopathology*; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D009687:Nuclear Proteins; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D003546:Cysteine Endopeptidases; C513261:Tnfaip3 protein, mouse