NF-κB Activation in primary CNS lymphoma. NF-κB transcriptional activation is regulated by multiple signals in PCNSL, including the MYD88/IRAK complex and the BCR complex consisting of CD79A and B. Activation of IRAK kinases via the oncogenic mutation of MYD88 at L265P impacts ∼55% of PCNSL cases. MYD88 is an adapter protein that mediates Toll-like receptor and interleukin-1 receptor signaling. Chronic active signaling via the BCR involving BTK likely cooperates with the MYD88/IRAK pathway in NF-κB activation. Other prosurvival signals include PIM kinases, the PI3K/mTOR, and JAK/STAT pathways. NF-κB target genes such as IRF-4, BCL-2, cyclin D2, RGS-13, and XBP-1 likely potentiate survival, proliferation, and invasion. IL, interleukin; MALT1, mucosa-associated lymphoid tissue; mTOR, mammalian target of rapamycin; PI3-K, phosphoinositide 3-kinase; PKC-β, protein kinase C beta; RGS, regulator of G-protein signaling; XBP-1, X-box binding protein-1.