title: Accelerated development of chronic lymphocytic leukemia in New Zealand Black mice expressing a low level of interferon regulatory factor 4.
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.
authors.affiliation: From the Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska 68198.
authors.forename: Shibin
authors.initials: S
authors.lastname: Ma
authors.forename: Vipul
authors.initials: V
authors.lastname: Shukla
authors.forename: Leilei
authors.initials: L
authors.lastname: Fang
authors.forename: Karen A
authors.initials: KA
authors.lastname: Gould
authors.forename: Shantaram S
authors.initials: SS
authors.lastname: Joshi
authors.forename: Runqing
authors.initials: R
authors.lastname: Lu
mesh_terms: D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000166:cytology; D004195:Disease Models, Animal; D005434:Flow Cytometry; D015973:Gene Expression Regulation, Leukemic; D055106:Genome-Wide Association Study; D006579:Heterozygote; D006706:Homeostasis; D006801:Humans; D050835:Interferon Regulatory Factors / Q000378:metabolism*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000503:physiopathology*; D051379:Mice; D008814:Mice, Inbred NZB; D008822:Mice, Transgenic; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D013154:Spleen / Q000166:cytology; D000099218:Interferon Regulatory Factor-4
chemical_list: D050835:Interferon Regulatory Factors; D000099218:Interferon Regulatory Factor-4
keywords: CLL; Genetic Polymorphism; IRF; IRF4; Leukemia; Lymphocyte; NZB; SNP; Transcription Factors; Tumor Cell Biology
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