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

Abstract

Summary 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.

IRF8-mutant B cell lymphoma evades immunity through a CD74-dependent deregulation of antigen processing and presentation in MHCII complexes

“…Cells were harvested and total RNA was isolated using TRIzol (Invitrogen) as we described ( 85 ). The RNA integrity and purity was determined by gel electrophoresis and by measuring 260/280 and 260/230 ratios in a nanodrop spectrophotometer, and cDNA generate with the High-Capacity cDNA Reverse Transcription Kit (Applied Biosystems).…”

IRF8-mutant B cell lymphoma evades immunity through a CD74-dependent deregulation of antigen processing and presentation in MHC CII complexes

“…Cells were harvested and total RNA was isolated using Trizol (Invitrogen) as we described 86 . The RNA integrity and purity was determined by gel electrophoresis and by measuring 260/280 and 260/230 ratios in a nanodrop spectrophotometer, and cDNA generate with the High-Capacity cDNA Reverse Transcription Kit (Applied Biosystems).…”

YTHDF1’s grip on CRC vasculature: insights into LINC01106 and miR-449b-5p-VEGFA axis

“…For example, LINC01106 can function as a sponge for miR-449b-5p, competitively binding and influencing the activity of miR-449b-5p, thus indirectly regulating VEGFA expression [47]. VEGFA is a crucial factor in angiogenesis, and alterations in its expression directly affect tumor vascular formation and growth [48]. Therefore, by investigating the role of LINC01106 in CRC, particularly how it affects tumor biological characteristics through m6A modification and the miR-449b-5p/VEGFA axis, new ideas and strategies for CRC treatment can be developed [47].…”