CBMS-04 Novel xenograft model to clarify tumor progressive mechanism and therapeutic target in primary central nervous system lymphoma Open Access

Primary central nervous system lymphoma (PCNSL) is a rare lymphoma of the central nervous system and has a dismal prognosis despite intensive chemotherapy. Recent genomic analyses have identified recurrent genetic alterations in Primary central nervous system lymphoma (PCNSL). However, lack of clinically representative PCNSL models has diminished our understanding of the pathogenic mechanisms of those genetic events. Here, we established 14 patient-derived orthotopic xenografts (PDOXs). Comprehensive analysis showed that PDOXs faithfully retained the phenotypic, metabolic, and genetic features with 100 % concordance of MYD88 and CD79B mutations present in immuno-competent PCNSL patients. Notably, orthotopic xenograft formation was consistently dependent on deregulated signaling through the RelA/p65-hexokinase 2 (HK-2) axis. MYD88/CD79B mutations and Pin1 activation, or LMP1 and Pin1 activation, converge on the RelA/p65-HK-2 signaling in immunocompetent and EBV-positive PCNSL, respectively. Genetic and pharmacological inhibition of this key signaling axis potently suppressed PCNSL tumor growth in vitro and in vivo. Additionally, our models further offer a platform for predicting clinical chemotherapeutics efficacy. Therefore, our models provide critical insights into pathogenic mechanisms and therapeutic discovery in PCNSL.