Consequences of PI3Kα/δ and BCL-2 inhibition in BCR-dependent DLBCLs with functional BCL-2 dependency. In blue: genetically modulated components of BCR/PI3K/TLR pathway and BCL-2 family. In red: functional consequences of PI3Kα/δ inhibition. In green: antiapoptotic BCL-2 family members. In purple: proapoptotic BCL-2 family members. In BCR-dependent NF-κB–low (GCB) DLBCLs, which often have inactivating mutations of PTEN and/or GNA13 (as in cluster 3), PI3Kα/δ blockade induced the proapoptotic HRK and BIM peptides and decreased the abundance of the antiapoptotic MCL-1 protein (A). In BCR-dependent NF-κB–high (ABC) DLBCLs with frequent MYD88^L265P and CD79B mutations (as in cluster 5), PI3Kα/δ inhibition decreased the abundance of NF-κB targets including the antiapoptotic BCL-xL and BFL-1 family members (B). In DLBCLs with genetic alterations of BCL2 (translocations, cluster 3; copy gain, cluster 5) and functional BCL-2 dependency, BCL-2 blockade released proapoptotic BH3 peptides from the antiapoptotic BCL-2 protein.