Deletion of Crebbp in the GC cooperates with BCL2 deregulation to promote lymphomagenesis. Deletion of Crebbp in the GC cooperates with BCL2 deregulation to promote lymphomagenesis. A, Incidence of B-cell lymphoproliferative diseases in the two cohorts. The percentage of animals with distinct lymphoma types is given inside the bar, and the total number of animals diagnosed with GC-derived lymphomas, out of the total analyzed, is shown on top. P < 0.05, Fisher exact test, two tails. Only heterozygous-null mice were included in the compound Crebbp floxed-BCL2 transgenic cohort because of the predominantly heterozygous pattern of mutations observed in human tumors (see Supplementary Fig. S6A–S6C). B, Histologic and immunohistochemical analysis of representative spleen sections from control mice and VavP-BCL2/Crebbp2fl/+/Cγ1-Cre mice [hematoxylin and eosin (H&E) staining; scale bar, 500 μm]. Double immunostaining for B220 and CD3 identifies the B- and T-cell zone. BCL6 serves as a GC-specific marker. An anti-human BCL2 antibody that does not cross-react with the murine BCL2 protein was used to specifically detect the expression of the VavP-BCL2 transgene, and is thus not staining the tissue from the control Cγ1-Cre–only animal. C, Southern blot analysis of EcoRI-digested DNA from representative lymphomas, hybridized with a murine JH3-4 probe. Tail genomic DNA controls for the germline immunoglobulin heavy-chain EcoRI fragment (6.5 kb). D, Enrichment plots of CREBBP core targets (top) or genes downregulated in Crebbp knockout GC B cells (bottom) in the rank of genes differentially expressed between DLBCL biopsies carrying intact CREBBP/EP300 alleles [n = 76; 30 GCB-type and 46 activated B-cell (ABC) type] and biopsies harboring CREBBP/EP300 genetic lesions (n = 28; 13 GCB-type and 15 ABC/unclassified). Jiyuan Zhang et al. Cancer Discov 2017;7:322-337 ©2017 by American Association for Cancer Research