GALNT3 is a novel target driving lymphomagenesis via O-glycosylation of FGFR2

Despite the dual roles of GALNT3 in various cellular processes related to tumorigenesis and solid tumors, the clinical and biological significance of GALNT3 in lymphomagenesis remains largely unknown. Herein, our bioinformatics analysis uncovers that GALNT3 dependent glucose metabolism was significantly elevated in DLBCL. Our DLBCL cohort study revealed that GALNT3 positivity is significantly associated with worse prognosis and clinical outcomes in DLBCL pathogenesis. Biologically, GALNT3 overexpression were found to promote DLBCL cell proliferation and cell cycle progression, while silencing GALNT3 inhibited lymphomagenesis. RNA-seq uncovers that GALNT3 upregulated FGFR2-MAPK signaling pathway in DLBCL. Moreover, protein mass spectrometry identified two potential O-glycosylation sites of FGFR2 (Thr319 and Ser299). Further point mutation of glycosylation sites, con?rmed that GALNT3 O-glycosylates FGFR2 through Thr319. Besides, in vitro and in vivo rescue experiments demonstrated that Thr319 is dispensable for GALNT3-FGFR2-MAPK induced lymphomagenesis. In vitro pharmacological inhibition of FGFR2 with a selective inhibitor Futibatinib further demonstrated that Futibatinib inhibits DLBCL cell growth, cell proliferation, induced cell cycle arrest, promoted cell apoptosis. Further in vivo study also indicated that combination of Futibatinib with chemotherapy demonstrated better anti-tumor activity relative to single drug therapy in DLBCL treatment. Collectively, our data highlight the importance of considering the GALNT3-FGFR2-MAPK signaling axis as an attractive therapeutic target for lymphomagenesis. Overall design: RNA-seq profiling of DLBCL cells and their GALNT3 overexpressing derivatives (ctrl,GALNT3-OE)