Hyper-N-glycosylated autoantigen-mediated CNS tropism. (A) PCNSL cells are derived from germinal center exit B cells that preferentially express BCR using the IGVH-4-34 genes that are known to produce antibodies with increased autoreactivity. Besides uniform activation of the BCR with CD79B mutations, PCNSL cells exhibit frequent cooccurring MYD88^L265P and infrequent CARD11 mutations, both known genetic alterations associated with tolerance failure and survival of autoantigen recognizing B cells (lower). In this issue of Blood, Thurner et al identify that PCNSL patients exhibit a hyper-N-glycosylated form of SAMD14 and neurabin-1 with high expression in the CNS tissue (upper). (B) Thurner et al discovered that the BCR of the PCNSL cells recognize the hyper-N-glycosylated forms of SAMD14 and neurabin-1, providing an attractive explanation that they have a canonical role in CNS tropism of this disease. (C) Concept of BCR-directed targeted therapy. A toxin is bound to the epitope of neurabin-1 that then bound specifically the tumor cells.