Besides single-gene mutations, several signaling and transcriptional pathways implicated in cell survival—such as phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), B-cell receptor (BCR)/BTK and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB)—are aberrantly activated in CLL, also due to the interactions with the protective tumor microenvironment2–5. This evidence concerns the gene BTK and B-cell chronic lymphocytic leukemia.