Characteristics of A20 gene polymorphisms in T-cell acute lymphocytic leukemia

Abstract

A20 is a repressor of NF-κB and was recently shown to be frequently inactivated by deletions or mutations in several types of lymphomas including T-cell lymphoma. Little is known about the characteristics of A20 mutations in T-cell acute lymphoblastic leukemia (T-ALL). In this study, we analyzed A20 polymorphisms and characterized their features in 11 cases with T-ALL, 30 samples from healthy Chinese individuals, and 3 cells lines including CCRF-CEM, Molt-4, and Toledo cells. Two frequent A20 polymorphisms were found: a CCT deletion at position 12384 and a nucleotide exchange (A to C) at position 13751 (rs2307859 and rs661561). The homozygous form (CC) of rs661561 was detected in all 10 cases with detectable T-ALL, while only 80% (24/30) of the healthy controls had this genotype. We found one T-ALL case without the above frequent single-nucleotide polymorphisms (SNPs) in which a T to G mutation at position 12486 was found, which results in an amino acid exchange (Phe127Cys; rs2230926). Similar results were found in Molt-4 cells, which lack the frequent SNPs but have a heterozygous polymorphism at position 13749 (C > T) (rs5029948). Interestingly, the T-ALL case with the Phe127Cys mutation and Molt-4 cells demonstrated a high A20 copy number as measured by real-time polymerase chain reaction amplification with three primer sets that cover different regions of the A20 gene, corresponding to a high A20 and low NF-κB expression level. In conclusion, we characterized the features of A20 polymorphisms in T-ALL, and found that a low frequency A20 mutation, which was thought to be involved in malignant T-ALL development, might function differently in T cell lymphomas.

Significant lethality following liver resection in A20 heterozygous knockout mice uncovers a key role for A20 in liver regeneration

“…53 Indeed, at least five of the A20 SNPs associate with lower A20 expression or activity in homozygous or heterozygous carriers of minor alleles, and hence could recap A20 HET. [54][55][56][57][58][59] On the basis of HapMap (Haplotype mapping) data, minor allele frequency of some of these SNPs is far from being negligible, especially in certain populations. For instance, the percentage of homozygous carriers of rs610604 minor allele (prevalent in patients with psoriasis and predicting higher coronary artery disease in diabetic patients) reaches 18% in Europeans and 32-50% in Africans, while the percentage of homozygous carriers of rs661561minor allele (associated with Grave's disease) reaches 37% in Europeans and up to 50% in Asians.…”

Genetic and Functional Associations with Decreased Anti-inflammatory Tumor Necrosis Factor Alpha Induced Protein 3 in Macrophages from Subjects with Axial Spondyloarthritis

“…In our study, the subjects with these previously described disease-risk variants exhibited a non-significant trend toward having lower TNFAIP3 levels (4/6 subjects at or below the control 25%). The association of alleles with higher TNFAIP3 levels has not been well described: there is only one report of a T-cell leukemia line bearing the rs5029948 variant with high TNFAIP3 expression level (64). Our numbers were too small to perform highly powered eQTL analyses, and the nominal association values found in this study should be followed up.…”

The role of aberrant proteolysis in lymphomagenesis

“…TNFAIP3 is primarily responsible for attenuation of NFκB signaling and thereby inhibits inflammation and tumorigenesis and TNF-mediated mediated apoptosis [128]. Mutational inactivation of TNFAIP3 by deletions, frameshift or nonsense mutations, and by promoter hypermethylation has been reported in several forms of B-cell and T-cell lymphoma [129–137]. TNFAIP3 inactivation by any mechanism contributes to lymphoma pathogenesis by promoting unchecked NFκB signaling and enhanced-cell survival [132].…”