An intronic polymorphism of IRF4 gene influences gene transcription in vitro and shows a risk association with childhood acute lymphoblastic leukemia in males

被引:45
|
作者
Do, Thuy N. [1 ]
Ucisik-Akkaya, Esma [1 ]
Davis, Charronne F. [1 ]
Morrison, Brittany A. [1 ]
Dorak, M. Tevfik [1 ]
机构
[1] HUMIGEN LLC, Inst Genet Immunol, Genom Immunoepidemiol Lab, Hamilton, NJ 08690 USA
来源
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE | 2010年 / 1802卷 / 02期
关键词
Genetic Predisposition to Disease; Lymphoblastic Leukemia; Acute; Childhood; Interferon Regulatory Factor 4; Polymorphism; Single Nucleotide; Luciferase Reporter Assay; Sex Effect; GENOME-WIDE ASSOCIATION; NF-KAPPA-B; INTERFERON REGULATORY FACTORS; LYMPHOCYTIC-LEUKEMIA; EXPRESSION PROFILE; FACTOR FAMILY; SUSCEPTIBILITY; CANCER; CELLS; MUM1/IRF4;
D O I
10.1016/j.bbadis.2009.10.015
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The interferon regulatory factor (IRF) family of DNA-binding proteins regulates expression of interferon-inducible genes with roles in the immune response and carcinogenesis. IRF4 is involved in the differentiation of B and T cells and is overexpressed in B-cell malignancies as a result of c-REL (NF-kappa B) hyperactivation. IRF4 polymorphisms are associated with susceptibility to chronic lymphoid leukemia (CLL) and non-Hodgkin lymphoma (NHL). We examined 13 IRF4 SNPs in 114 cases of childhood acute lymphoblastic leukemia (ALL) and 388 newborn controls from Wales (U.K.) using TaqMan assays. IRF4 intron 4 SNP rs12203592 showed a male-specific risk association (OR = 4.4. 95% CI = 1.5 to 12.6, P = 0.007). Functional consequences of the C>T substitution at this SNP were assessed by cell-based reporter assays using three different cell lines. We found a repressive effect of the rs12203592 wildtype allele C on IRF4 promoter activity (P<0.001) but no repression by the variant allele in any cell line tested. Thus, homozygosity for the rs12203592 variant allele would result in increased IRF4 expression. This increase would be compounded by high levels of NF-kappa B activity in males due to the absence of estrogen. IRF4 differs from other IRFs in its anti-interferon activity which interferes with immune surveillance. We propose that a detailed study of IRF4 can provide information on the mechanism of the sex effect and the role of immune surveillance in childhood ALL development. (C) 2009 Elsevier B.V. All rights reserved.
引用
收藏
页码:292 / 300
页数:9
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