Diffuse Large B-Cell Lymphoma (DLBCL) is an aggressive malignancy of which one-third of diagnosed patients ultimately die. New treatment paradigms for relapsedrefractory patients are needed. Almost all DLBCL tumours express a B-cell receptor (BCR), which is a cell surface antigen receptor of immunoglobulin in tandem with the signalling adapters CD79A and CD79B. Over the last 2 decades, the importance of signals emanating from the BCR have gained prominence in how we understand oncogenic signalling in DLBCL. Multiple agents targeting BCR signalling have been tried in large clinical trials, but none have yet succeeded in altering front-line therapy. A greater understanding of BCR biology is needed. Here, I studied regulators of the BCR using whole genome CRISPR screens. First, I created an assay for internalisation of the BCR and combined it with a sorted CRISPR screen to try to understand how the BCR transits to intracellular signalling platforms. Next, I used the anti-CD79B antibody drug conjugate Polatuzumab-Vedotin (POLA-V) as a tool to study regulators of surface BCR. By combining drug CRISPR screens with surface-CD79B sorted screens, I uncovered both regulators of synergy and resistance to an important therapeutic and discovered regulators of BCR protein levels. Mechanistically, I found specific glycosylated residues on CD79A and CD79B that block Polatuzumab-Vedotin from binding its target, and I found that KLHL6 targets CD79B for degradation via CD79B K219. Based on these findings, I identified strategies for enhancing POLA-V killing by removing cell surface sialic acid. In a second line of work, I revealed a novel role for the E3 ligase KLHL6 in suppressing BCR complex cell surface expression in the germinal centre. These findings have clinical implications for patients receiving POLA-V and further our understanding of a regulator of the immune response.