Sustained NF-kappaB activity in chronic lymphocytic leukemia is independent of genetic and epigenetic alterations in the TNFAIP3 (A20) locus.
Inappropriate nuclear factor (NF) κB activity is one major hallmark of B-cell malignancies and chronic lymphocytic leukemia (CLL). NFκB-dependent genes are involved in antiapoptosis, cell proliferation and metastasis and are responsible for survival and proliferation of tumors. However, the mechanisms of NFκB activity in CLL still need to be elucidated. Previously, we identified translocations in a region on chromosome 6q that encodes tumor necrosis factor alpha-induced protein 3, which is a key player in negative feedback loop regulation of NFκB. Inactivation of this ubiquitin-editing enzyme is involved in immunopathologies and in tumorigenesis. Frequent mutations in the A20 locus--leading to sustained NFκB activity--could be shown to play a dominant role in development of different B-cell malignancies. To check if A20 is involved in upregulation of NFκB activity in CLL, we sequenced Exons 2-9 of the A20 gene in 55 CLL DNA samples. Furthermore, we determined the methylation status of the promoter region in 63 CLL DNA samples and compared to 10 control DNAs of B cells from healthy donors. Contrary to reports from other B-cell malignancies, the A20 region showed neither mutations nor aberrant DNA methylation. Moreover, its expression could be confirmed by immunoblotting and showing comparable results to healthy B cells. These results indicate that malignant development in CLL differs from most of other B-cell malignancies, which show frequent inactivation of A20.
Frenzel
Lukas P
LP
Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany. Lukas.frenzel@uk-koeln.de
Claus
Rainer
R
Plume
Nadine
N
Schwamb
Janine
J
Konermann
Carolin
C
Pallasch
Christian P
CP
Claasen
Julia
J
Brinker
Reinhild
R
Wollnik
Bernd
B
Plass
Christoph
C
Wendtner
Clemens-Martin
CM
D002896:Chromosomes, Human, Pair 6; D019175:DNA Methylation; D004268:DNA-Binding Proteins; D044127:Epigenesis, Genetic; D005091:Exons; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic; 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