Transcriptomic profiling of an in vivo diffuse large B-cell lymphoma model reveals molecular programs underlying CNS dissemination

Secondary central nervous system involvement (sCNSi) is a fatal complication of diffuse large B-cell lymphoma (DLBCL), yet its molecular determinants remain poorly understood. To investigate the mechanisms underlying CNS-preferential dissemination, we established an in vivo DLBCL xenograft model using two representative cell lines, OCI-LY19 and Toledo, followed by transcriptomic profiling of lymphoma cells isolated from the brain, peripheral organs, and parental cultures. Transcriptomic analyses revealed gene signatures associated with CNS-preferential dissemination, which were further evaluated in RNA-seq data from diagnostic tissues of patients with (n = 19) or without (n = 16) sCNSi. CNS tropism of DLBCL cells was associated with increased expression of genes involved in PI3K-Akt-mTOR and ARF6 trafficking signaling and decreased expression of sphingosine-1-phosphate receptor signaling. Patient-derived transcriptomes exhibited enrichment of pathways that were functionally related to the gene signatures observed in the xenograft model. These findings suggest that CNS-preferential dissemination in DLBCL is associated with coordinated signaling involving PI3K/ARF6 activation and suppression of S1P-mediated pathways, providing molecular insights with potential implications for risk stratification and therapeutic targeting in sCNSi.