Jo et al demonstrate that an increase in LUBAC activity via elevated levels of HOIP cooperates with the MyD88 L252P activating mutation in mice to induce B lymphomas that resemble ABC DLBCL. The lymphomas are thought to arise in part from a HOIP-mediated cellular protection from DNA damage events, leading to the accumulation of somatic mutations that likely play a role in B-cell transformation. The authors identify Thiolutin as an inhibitor of HOIP E3 ligase activity in vitro that can inhibit lymphoma growth in vivo.