Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, NE; and.
Blood. 2013 Oct 17;122(16):2848-55. doi: 10.1182/blood-2013-03-492769. Epub 2013 Aug 7.
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.
干扰素调节因子 4（IRF4）是 B 细胞发育和功能的关键转录调节因子。最近的全基因组单核苷酸多态性（SNP）关联研究确定 IRF4 是慢性淋巴细胞白血病（CLL）的主要易感基因。尽管位于 IRF4 基因中的 SNPs 与 CLL 患者中 IRF4 的下调有关，但 IRF4 水平低是否对 CLL 发展至关重要仍不清楚。在啮齿动物中，CLL 细胞来源于 B1 细胞，其在免疫球蛋白重链 Vh11 敲入小鼠中显著扩增。我们将 Vh11 敲入等位基因引入 IRF4 缺陷型小鼠（IRF4(-/-)Vh11）。在这里，我们报告 IRF4(-/-)Vh11 小鼠自发发展为早期发病的 CLL，具有 100%的外显率。进一步的分析表明，IRF4(-/-)Vh11 CLL 细胞主要在脾脏中增殖，并表达高水平的 Mcl-1。IRF4(-/-)Vh11 CLL 细胞对凋亡有抗性，但在 IRF4(-/-)Vh11 CLL 细胞中重建 IRF4 表达可抑制其存活。因此，我们的研究首次证明了低水平的 IRF4 与 CLL 的发展之间存在因果关系。此外，我们的研究结果确立了 IRF4(-/-)Vh11 小鼠作为一种新的 CLL 小鼠模型，不仅对于解析 CLL 的分子发病机制具有重要价值，而且还可用于治疗目的。
