Refined cell-of-origin subtyping identified patients harboring GCB and DZsig+ relapsed/refractory tumors in cases with primary refractory disease with remarkably poor outcomes, and comparative analysis of genomic features between relapsed and diagnostic samples identified subtype-specific mechanisms of therapeutic resistance driven by frequent alteration to MYC, BCL2, BCL6, and TP53 among additional strong lymphoma driver genes. Here, BCL2 is linked to lymphoma.