A role for IRF4 in the development of CLL

Interferon regulatory factor 4 (IRF4) is a critical transcriptional regulator of B-cell development and function. A recent genome-wide single-nucleotide polymorphism (SNP) association study identified IRF4 as a major susceptibility gene in chronic lymphocytic leukemia (CLL). Although the SNPs locate...

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Bibliographic Details
Published in:Blood 2013-10, Vol.122 (16), p.2848-2855
Main Authors: Shukla, Vipul, Ma, Shibin, Hardy, Richard R., Joshi, Shantaram S., Lu, Runqing
Format: Article
Language:English
Subjects:
Alleles
Animals
Apoptosis
Cell Transplantation
Crosses, Genetic
Flow Cytometry
Gene Expression Regulation, Leukemic
Interferon Regulatory Factors - metabolism
Leukemia, Lymphocytic, Chronic, B-Cell - metabolism
Lymphoid Neoplasia
Mice
Mice, Inbred C57BL
Mice, Transgenic
Mutation
Myeloid Cell Leukemia Sequence 1 Protein - metabolism
Phenotype
Spleen - metabolism
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Summary:Interferon regulatory factor 4 (IRF4) is a critical transcriptional regulator of B-cell development and function. A recent genome-wide single-nucleotide polymorphism (SNP) association study identified IRF4 as a major susceptibility gene in chronic lymphocytic leukemia (CLL). Although the SNPs located in the IRF4 gene were linked to a downregulation of IRF4 in CLL patients, whether a low level of IRF4 is critical for CLL development remains unclear. In rodents, CLL cells are derived from B1 cells whose population is dramatically expanded in immunoglobulin heavy chain Vh11 knock-in mice. We bred a Vh11 knock-in allele into IRF4-deficient mice (IRF4−/−Vh11). Here, we report that IRF4−/−Vh11 mice develop spontaneous early-onset CLL with 100% penetrance. Further analysis shows that IRF4−/−Vh11 CLL cells proliferate predominantly in spleen and express high levels of Mcl-1. IRF4−/−Vh11 CLL cells are resistant to apoptosis but reconstitution of IRF4 expression in the IRF4−/−Vh11 CLL cells inhibits their survival. Thus, our study demonstrates for the first time a causal relationship between low levels of IRF4 and the development of CLL. Moreover, our findings establish IRF4−/−Vh11 mice as a novel mouse model of CLL that not only is valuable for dissecting molecular pathogenesis of CLL but could also be used for therapeutic purposes. •IRF4−/−Vh11 mice develop spontaneous CLL at 100% penetrance, indicating that a low level of IRF4 is critical for CLL development.•IRF4−/−Vh11 mice are a novel mouse model of CLL.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2013-03-492769