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•In DLBCLs with MYD88L265Pand CD79BY196Falterations, MYD88L265Pselectively increased proximal BCR signaling and survival via DOCK8.•MYD88L265P/DOCK8–enhanced proximal BCR signaling is a basis for the increased sensitivity of MYD88L265P/CD79BY196FDLBCLs to BTK blockade.

Diffuse large B cell lymphoma (DLBCL) is the most common Non-Hodgkin lymphoma and originates from transformed germinal center-experienced B cells. Traditionally, DLBCL has been divided into two subtypes, depending on whether the transcriptional profile of the tumor relates to an activated B cell or a germinal center B cell (ABC and GCB DLBCL, Alizadeh et al., 2000). More recent efforts classified DLBCL cases based on their genetic aberrations and identified several clusters with distinct mutational profiles (Chapuy et al., 2018, Schmitz et al., 2018, Wright et al., 2020). The MCD/C5 cluster is characterized by recurrent mutations in MYD88, PRDM1and frequent amplifications of BCL2, amongst others. We recently showed that mice harboring a B cell-specific Myd88 L252Pmutation (orthologous position of the human p.L265P mutation) develop B cell proliferation and occasional transformation into DLBCL (Knittel et al., 2016). Lymphomagenesis is further increased when Myd88 L252Pis combined with BCL2overexpression and a genetically engineered block in plasmacytic differentiation by loss of Prdm1or overexpression of Spib(Flümann et al., 2021).

Diffuse large B-cell lymphoma (DLBCL) is a genetically heterogeneous disease comprised of five subtypes including a subset of poor-prognosis activated B cell (ABC)-enriched tumors with frequent MYD88L265Pmutations, often in association with CD79Balterations (Cluster 5 DLBCLs) (Nat. Med. 2018; 24:679-690). Primary central nervous system lymphomas (PCNSLs) and primary testicular lymphomas (PTLs) have similar genetic signatures including recurrent MYD88L265Pmutations and concurrent CD79Balterations (Blood 2016; 127: 869-81). These findings prompted us to evaluate a potential role for MYD88L265Pin proximal B-cell receptor (BCR) signaling, in addition to its defined function as an intermediary in the Toll-Like Receptor (TLR) pathway and downstream NF-kB activation.