In diffuse large B-cell lymphoma (DLBCL), angiogenesis and MYC expression were associated with a poor prognosis. Although MYC encourages neo-vasculature formation, it was unknown if MYC dysregulation in DLBCL contributed to angiogenesis. Analyzing the connection could reveal new pathogenic regulatory circuits and anti-angiogenic tactics in DLBCL. For a study, researchers showed that, regardless of dual expressor status or cell-of-origin categorization, MYC expression positively correlates with vascular endothelial growth factor (VEGF) expression and angiogenesis in primary DLBCL biopsies.

They discovered a link between MYC and VEGFA expression, which was supported by sizable datasets of mature B-cell tumors. They discovered that the second messenger cyclic-AMP (cAMP) was a strong inhibitor of MYC expression, VEGFA secretion, and angiogenesis in DLBCL under normoxia using DLBCL cell lines and patient-derived xenograft models. The primary regulator of VEGFA/angiogenesis in low oxygen conditions, hypoxia-inducible factor 1α, was one of the sites that cAMP moved to in hypoxia and was repressed.

Finally, they showed that the cAMP/PDE4 axis exerts further anti-angiogenesis by specifically targeting the lymphoma microenvironment. In conclusion, clinical grade PDE4 inhibitors may modulate cAMP levels, which has cell and non-cell autonomous anti-angiogenic effect in DLBCL. MYC may directly contribute to DLBCL angiogenesis.