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.
Highlights
A genome-wide SNP association study has linked low levels of IRF4 with the development of chronic lymphocytic leukemia (CLL)
Our result shows that New Zealand Black (NZB) IRF4ϩ/Ϫ CLL cells were B220lowIgMhi IgDlowCD21ϪCD23ϪCD43ϩ, a surface phenotype that resembles B1 cells, from which they were derived (Fig. 2A)
Our result shows that the Ca2ϩ influx triggered by B cell receptors (BCR) signaling was comparable between MigR1 and MigIRF4 transduced cells, indicating that a transient increase in the IRF4 expression level cannot attenuate BCR signaling in NZB IRF4ϩ/Ϫ CLL cells
Summary
A genome-wide SNP association study has linked low levels of IRF4 with the development of CLL. A recent genome-wide SNP association study identified IRF4 as a major susceptibility gene for chronic lymphocytic leukemia (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. NZB IRF4؉/؊ CLL cells are resistant to apoptosis, high levels of IRF4 inhibit their survival. High levels of IRF4 reduce the survival of MEC-1 human CLL cells. We provide evidence that high levels of IRF4 suppressed Akt and promoted apoptosis in CLL cells
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