In the ABC DLBCL subtype, EBF1, IRF4, CARD11, MYD88, and IKBKB knockout produced significant reduction in cell viability, whereas in GCB DLBCL, the knockout of ZBTB7A, XPO1, TGFBR2, and PTPN6 was more selectively lethal to the subtype. Here, IKBKB is linked to diffuse large B-cell lymphoma.