BCR-dependent cases are highly sensitive to inhibition of SYK, BTK, and PI3K. MEK and mTOR activation occur downstream of BCR. Most U-CLL patients belong to this group. In contrast, there is a group of CLL where cells receive survival signals from alternative sources (e.g., cytokines/chemokines) and whose drug response pattern is inconsistent with canonical BCR signaling, as the effect of inhibiting mTOR is greater than for BTK. PI3K, phosphatidylinositol 3-kinase; IKKβ, IκBα-Kinase-complexes; AMPK, AMP-activated protein kinase; TSC1/2, hamartin/tuberin; PDK1, pyruvate dehydrogenase kinase 1; SGK3, serine/threonine-protein kinase; PLC, phosphoinositide-phospholipase C; PKCβ, protein kinase C β; CBM, CARMA1-Bcl10-MALT1 complex; mTOR, mechanistic target of rapamycin; SYK,spleen tyrosine kinase; BTK, Bruton’s tyrosine kinase; Lyn, tyrosine kinase Lyn.