A model of early- and late-divergent modes of DLBCL relapse. In both modes, the early B lymphoma precursors arise from normal B cells that sustain key genetic lesions, such as mutations occurring at epigenetic modifying enzymes, that is, EP300, KMT2D, and SETDB1. In the late-divergent mode (top panel), after acquiring additional facilitator mutations, early B lymphoma precursors develop into DLBCL-containing subclones that have similar but slightly different SHM profiles (indicated by different shades of red) due to ongoing SHM. After treatment, one or few subclones survive and develop into relapse disease, potentially by acquiring additional mutations. In the early-divergent mode (bottom panel), early B lymphoma precursor cells progress into initial DLBCL-containing subclones that have similar SHMs (indicated by different shades of red) and one or few minor subclones (depicted by blue) that have unique SHM profiles vastly different from the subclones of the major diagnostic clone (the red ones), indicating divergence during clonal expansion of the tumor. This minor clone later survives or escapes chemotherapy, and develops into a relapse tumor that has a diverged subclonal origin from the diagnosis tumor (blue versus red).