In mature B-cell malignancies, chromosomal translocations often juxtapose an oncogenic locus to the regulatory regions of the immunoglobulin genes. These genomic rearrangements can associate with specific clinical/pathological sub-entities and inform diagnosis and treatment decisions. Recently, we characterized the t(14;16)(q32;q24) in diffuse large B-cell lymphoma (DLBCL), and showed that it targets the transcription factor IRF8, which is also somatically mutated in ~10% of DLBCLs. IRF8 regulates innate and adaptive immune responses mediated by myeloid/monocytic and lymphoid cells. While the role of IRF8 in human myeloid/dendritic-cell disorders is well established, less is known of its contribution to the pathogenesis of mature B-cell malignancies. To address this knowledge gap, we generated the Eµ-Irf8 mouse model, which mimics the IRF8 deregulation associated with t(14;16) of DLBCL. Eµ-Irf8 mice develop normally and display peripheral blood cell parameters within normal range. However, Eµ-Irf8 mice accumulate pre-pro-B-cells and transitional B-cells in the bone marrow and spleen, respectively, suggesting that the physiological role of Irf8 in B-cell development is amplified. Notably, in Eµ-Irf8 mice, the lymphomagenic Irf8 targets Aicda and Bcl6 are overexpressed in mature B-cells. Yet, the incidence of B-cell lymphomas is not increased in the Eµ-Irf8 model, even though their estimated survival probability is significantly lower than that of WT controls. Together, these observations suggest that the penetrance on the Irf8-driven phenotype may be incomplete and that introduction of second genetic hit, a common strategy in mouse models of lymphoma, may be necessary to uncover the pro-lymphoma phenotype of the Eµ-Irf8 mice.

在成熟的B细胞恶性肿瘤中，染色体易位通常将致癌基因位点与免疫球蛋白基因的调节区并列。这些基因组重排可以与特定的临床/病理亚实体相关联，并为诊断和治疗决策提供依据。最近，我们表征了弥漫性大B细胞淋巴瘤（DLBCL）中的t（14; 16）（q32; q24），并表明它靶向转录因子IRF8，在约10％的DLBCL中也会发生体细胞突变。IRF8调节由髓样/单核细胞和淋巴样细胞介导的先天性和适应性免疫反应。尽管IRF8在人类髓样/树突状细胞疾病中的作用已得到充分确立，但对它对成熟B细胞恶性肿瘤发病机理的贡献知之甚少。为了解决这一知识鸿沟，我们生成了Eµ-Irf8小鼠模型，该模型模仿了与DLBCL的t（14; 16）相关的IRF8失调。Eµ-Irf8小鼠正常发育并显示正常范围内的外周血细胞参数。但是，Eμ-Irf8小鼠分别在骨髓和脾脏中积聚了前pro-B细胞和过渡性B细胞，这表明Irf8在B细胞发育中的生理作用被放大了。值得注意的是，在Eµ-Irf8小鼠中 在成熟的B细胞中，淋巴瘤性Irf8靶标Aicda和Bcl6过表达。然而，即使E-Irf8模型的估计生存率明显低于野生型对照，其B细胞淋巴瘤的发病率也没有增加。在一起，这些观察结果表明，对Irf8驱动的表型的外显力可能是不完全的，并且可能有必要引入第二种遗传击中（在淋巴瘤小鼠模型中的常见策略）来揭示Eµ-Irf8小鼠的前淋巴瘤表型。