Generation and Characterization of the Eμ-Irf8 mouse model

• Published in: Cancer genetics 2020-07, Vol.245, p.6-16
• Main Authors: Qiu, Zhijun, Holder, Kenneth N., Lin, An-Ping, Myers, Jamie, Jiang, Shoulei, Gorena, Karla M., Kinney, Marsha C., Aguiar, Ricardo C.T.
• Format: Article
• Language: English
• ISSN: 2210-7762
• DOI: 10.1016/j.cancergen.2020.05.002

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, confirming that this model amplifies the physiologic role of Irf8 in B-cell development. 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.