Accelerated Development of Chronic Lymphocytic Leukemia in New Zealand Black Mice Expressing a Low Level of Interferon Regulatory Factor 4

被引:18
|
作者
Ma, Shibin [1 ]
Shukla, Vipul [1 ]
Fang, Leilei [1 ]
Gould, Karen A. [1 ]
Joshi, Shantaram S. [1 ]
Lu, Runqing [1 ]
机构
[1] Univ Nebraska Med Ctr, Dept Genet Cell Biol & Anat, Omaha, NE 68198 USA
基金
美国国家卫生研究院;
关键词
B-CELL DEVELOPMENT; TRANSCRIPTION FACTORS; TUMOR-SUPPRESSOR; IRF FAMILY; LOCUS; TCL1; DIFFERENTIATION; RECEPTOR; MOUSE; PHOSPHORYLATION;
D O I
10.1074/jbc.M113.475913
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
A recent genome-wide SNP association study identified IRF4 as a major susceptibility gene for chronic lymphocytic leukemia (CLL). Moreover, the SNPs located in the 3' UTR of the IRF4 gene have been linked to a down-regulation of IRF4. However, whether a low level of IRF4 is critical for CLL development remains unclear. New Zealand Black (NZB) mice are a naturally occurring, late-onset mouse model of CLL. To examine the role of a reduced level of IRF4 in CLL development, we generated, through breeding, IRF4 heterozygous mutant mice in the NZB background (NZB IRF4(+/-)). Our results show that CLL development is accelerated dramatically in the NZB IRF4(+/-) mice. The average onset of CLL in NZB mice is 12 months, but CLL cells can be detected in NZB IRF4(+/-) mice at 3 months of age. By 5 months of age, 80% of NZB IRF4(+/-) mice developed CLL. CLL cells are derived from B1 cells in mice. Interestingly, NZB IRF4(+/-) B1 cells exhibit prolonged survival, accelerated self-renewal, and defects in differentiation. Although NZB IRF4(+/-) CLL cells are resistant to apoptosis, high levels of IRF4 inhibit their survival. High levels of IRF4 also reduce the survival of MEC-1 human CLL cells. Our analysis further reveals that high levels of IRF4 suppress Akt activity and can do so without the IRF4 DNA binding domain. Thus, our findings reveal a causal relationship between a low level of IRF4 and the development of CLL and establish IRF4 as a novel regulator in the pathogenesis of CLL.
引用
收藏
页码:26430 / 26440
页数:11
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