PI3Kδ is activated after SYK-mediated phosphorylation of CD19, which provides docking sites for PI3Kδ. PI3Kδ generates the lipid second-messenger molecule phosphatidylinositol(3,4,5)P3 (PIP3), which binds the PH domains of AKT and BTK. BTK is also regulated directly via SYK-mediated phosphorylation of BLNK. The activation of PLC-γ2 downstream of BTK is essential for generating the second-messenger molecules diacylglycerol and Ca²⁺ (not shown), which in turn control various transcription factors and contribute to the activation of RAS. RAS is at the apex of the MAPK signaling pathway, which is controlled by sequential activation of the kinases RAF, MEK, and ERK. Remarkably, Murali et al found activating mutations in genes encoding RAS, RAF, and MEK (mutated genes shown in italics in the figure). Strikingly, they found no mutations in genes typically associated with increased PI3K signaling in other cancer types (PIK3CA, PTEN, and AKT1-2, and -3). A search of 1308 CLL samples from The Cancer Genome Atlas returned no significant mutation in any of these genes (K.O., unpublished observations). Murali and colleagues therefore propose that PI3Kδ inhibitors such as idelalisib be combined with MAPK inhibitors, such as the MEK inhibitor trametinib, to circumvent adaptive resistance to therapy. Professional illustration by Somersault18:24.