The Novel Immunocompetent Eµ-SOX11CCND1 Mouse Model Molecularly and Phenotypically Mimics Human Mantle Cell Lymphoma

Mantle Cell Lymphoma (MCL) is an incurable blood cancer affecting older adults with a median survival of 80 months. There is a great need for novel therapies and immunocompetent pre-clinical models that effectively mimic the tumor micro-environment (TME). Most MCL murine models are patient derived xenografts (PDXs), which are immunocompromised, making them suboptimal to test immunotherapies. Previous attempts at an immunocompetent model were less than optimal with limited pathology, narrow phenotype, or the use of genes not implicated in MCL. Here, we present a novel transgenic, immunocompetent mouse model for MCL by expressing two key MCL genes, SRY-Box Transcription Factor 11 (SOX11), and Cyclin D1 (CCND1) under the Eµ enhancer in C57BL/6 mice. The resulting double transgenic mice showed lethal expansion of B1a (CD5+CD19+CD23-) sub-B cell population in lymphatic organs, as well as the liver, lung, and kidney. We subsequently show this population can further adoptively transferred to healthy mice, which develop aggressive MCL. Passage one was profiled and found to express key human MCL driver genes, as well as cell surface marks, including the immune suppressive PD-1 and PDL-1. This model is resistant to ibrutinib and venetoclax, medications currently used for MCL, but highly responsive to a protein arginine methyltransferase 5 (PRMT5) inhibitor (OS 18 vs. 67 days p<0.01), supporting our previous work showing PRMT5 as a promising target for MCL. This study provides the pathological and genetic characterization needed to utilize the Eµ-SOX11CCND1 model of MCL to improve the preclinical research of immunotherapeutic and immunomodulatory agents.