PDE4B signaling interactions highlight novel opportunities for combined therapeutic approaches in DLBCL. We showed that in normal and malignant B-lymphocytes cAMP, at least in part via down-modulation of the tyrosine kinase SYK, inhibits the PI3K/AKT/mTOR pathway, thus curtailing cell proliferation and inducing apoptosis. As PDE4B inactivates cAMP, it abrogates these growth inhibitory effects, and in subsets of DLBCL, it may contribute to the abnormally elevated activity of SYK and PI3K/AKT/mTOR. Pharmacologic inhibition of PDE4B should restore the intracellular levels of cAMP, reestablish growth suppression and apoptosis, and potentially improve the efficacy of various agents that impinge on this pathway. Indeed, in proof-of-principle experiments, we showed that genetic modulation of PDE4B increase the effectiveness of a SYK inhibitor. This concept is timely and its clinical implementation a realistic goal as exemplified by availability of series of relevant compounds already in clinical trials for lymphomas (http://clinicaltrials.gov/).