Critical signaling pathways for survival and apoptosis in CLL. The BCR signaling pathway is constitutively activated and leads to several effects, including proliferation, maturation, and migration in CLL. This pathway is pharmacologically blocked by several inhibitors, such as ibrutinib (Bruton tyrosine kinase inhibitor) or idelalisib (PI3K isoform δ inhibitor). At the same time, CLL cells are skewed toward a phenotype evading apoptosis. Apoptosis can be triggered by inducing DNA damage (purine analogs, alkylating agents) or by blocking BCL-2 protein using the BH3 mimetic drug venetoclax. Bak, Bcl-2 homologous antagonist killer; Bax, bcl-2–like protein 4; BIM, B-cell lymphoma 2 interacting mediator of cell death; BLNK, B cell linker; BTK, Bruton tyrosine kinase; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor κB; PLC, phospholipase C; PUMA, p53 upregulated modulator of apoptosis; SYK, spleen tyrosine kinase.