Work

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

Year: 2013

Type: article

Abstract: 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. Background: A genome-wide SNP association study has linked low levels of IRF4 with the development of CLL. Results: Low levels of IRF4 disrupt homeostasis of B1 B cells and promote survival of CLL cell. Conclusion: Our results demonstrate a causal relationship between low levels of IRF4 and the development of CLL. Significance: We establish IRF4 as a critical regulator in the pathogenesis of CLL.

Source: Journal of Biological Chemistry

DOI: 10.1074/jbc.m113.475913

Authors: Shibin Ma, Vipul Shukla, Leilei Fang, Karen A. Gould, Shantaram S. Joshi, Runqing Lu

Institution: University of Nebraska Medical Center

Language: English

Topic: Chronic Lymphocytic Leukemia Research

Subfield: Genetics

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $3,430