Cyclic-AMP signalling, MYC and hypoxia-inducible factor 1α intersect to regulate angiogenesis in B-cell lymphoma

Purushoth Ethiraj, Binu Sasi, KENNETH HOLDER, An Ping Lin, Zhijun Qiu, Carine Jaafar, Alia Elkhalili, Parth Desai, Annapurna Saksena, Jacob P. Ritter, Ricardo C.T. Aguiar

Research output: Contribution to journalArticlepeer-review

Abstract

Angiogenesis and MYC expression associate with poor outcome in diffuse large B-cell lymphoma (DLBCL). MYC promotes neo-vasculature development but whether its deregulation in DLBCL contributes to angiogenesis is unclear. Examination of this relationship may uncover novel pathogenic regulatory circuitry as well as anti-angiogenic strategies in DLBCL. Here, we show that MYC expression positively correlates with vascular endothelial growth factor (VEGF) expression and angiogenesis in primary DLBCL biopsies, independently of dual expressor status or cell-of-origin classification. We found that MYC promotes VEGFA expression, a correlation that was validated in large datasets of mature B-cell tumours. Using DLBCL cell lines and patient-derived xenograft models, we identified the second messenger cyclic-AMP (cAMP) as a potent suppressor of MYC expression, VEGFA secretion and angiogenesis in DLBCL in normoxia. In hypoxia, cAMP switched targets and suppressed hypoxia-inducible factor 1α, a master regulator of VEGFA/angiogenesis in low oxygen environments. Lastly, we used the phosphodiesterase 4b (Pde4b) knockout mouse to demonstrate that the cAMP/PDE4 axis exercises additional anti-angiogenesis by directly targeting the lymphoma microenvironment. In conclusion, MYC could play a direct role in DLBCL angiogenesis, and modulation of cAMP levels, which can be achieved with clinical grade PDE4 inhibitors, has cell and non-cell autonomous anti-angiogenic activity in DLBCL.

Original languageEnglish (US)
JournalBritish Journal of Haematology
DOIs
StateAccepted/In press - 2022

Keywords

  • angiogenesis
  • cyclic-AMP
  • hypoxia
  • lymphoma
  • MYC

ASJC Scopus subject areas

  • Hematology

Fingerprint

Dive into the research topics of 'Cyclic-AMP signalling, MYC and hypoxia-inducible factor 1α intersect to regulate angiogenesis in B-cell lymphoma'. Together they form a unique fingerprint.

Cite this