The cyclic-AMP/PDE4B axis in the lymphoma cell andits microenvironment. Antigen binding activates the BCR, a process initiated by phosphorylation of the immunoreceptor tyrosine-based activation motifs (ITAMs) on CD79A and CD79B, and amplified by a cascade of events that involve multiple protein and lipid kinases. These “upstream” events culminate in the activation of downstream, prosurvival, signaling pathways, including among others NF-κB, MAPK, and the AKT/mTOR complex 1 (mTORC1).^42,43  Cyclic-AMP (cAMP) downmodulates this positive signaling wave by suppressing SYK and PI3Kδ activity.^6,7  cAMP may also use its effector PKA to activate CSK, which inhibits SFKs via C-terminal phosphorylation. Decreased SFK activity may directly, or via SYK, limit p85 phosphorylation and thus PI3K function.¹⁵  This PKA-CSK-SFK interplay has been demonstrated in T lymphocytes and endothelial cells, but not yet in normal and malignant B cells.^21,31  In B-cell lymphoma and related malignancies, the inhibitory effects of cAMP are abrogated by PDE4, which hydrolyzes this second messenger to the inactive adenosine monophosphate (AMP), thus sustaining BCR activity and defining a prosurvival profile.^5-8,16  Downstream to PI3K/AKT, the cAMP/PDE4 axis also impinges on the lymphoma microenvironment. In B-cell lymphomas with high PDE4B levels, cAMP is hydrolyzed to AMP, resulting in higher AKT-driven VEGFA expression in the tumor cell, excessive secretion in the tumor milieu, and enhanced angiogenesis.⁹  cAMP, in a PDE4-dependent manner, also suppresses the survival and proliferation of endothelial cells,²⁸  downmodulates the secretion of various proinflammatory cytokines, and increases the number of Tregs.^51-54  The PDE4 inhibitor roflumilast abrogates cAMP hydrolysis, elevates the intracellular levels of this second messenger, and restores its suppressive effects in the lymphoma cell and the microenvironment. PLC, phospholipase C; TNF, tumor necrosis factor.