biostudies-literatureChen JLSzu-Yuan Research Foundation of Internal MedicineMelissa Lee Cancer FoundationTaipei City HospitalTaipei Veterans General HospitalNational Science and Technology CouncilDr. Morris ChangTeh-Tzer Study Group for Human Medical Research Foundation of Taiwan345https://www.ebi.ac.uk/biostudies/studies/S-EPMC12578764biostudies-literatureUnknown25(1)Diffuse large B-cell lymphoma (DLBCL) is characterized by molecular complexity and heterogeneity. The SET oncoprotein is overexpressed in B-cell chronic lymphocytic leukemia and non-Hodgkin lymphoma. Acting as an intrinsic inhibitor of the tumor suppressor protein phosphatase 2A (PP2A), targeting SET has shown anti-cancer activity. In this study, we investigated the molecular mechanism of SET antagonism in DLBCL. Overexpression of SET resulted in decreased phosphatase activities of PP2A and SHP-1, while activating Lyn. Conversely, SET inhibition, either through antagonists or siRNA, led to the activation of PP2A and SHP-1, resulting in the inactivation of Lyn. Analysis of public datasets revealed upregulation of Lyn in late-stage DLBCL samples, which was associated with a worse outcome. EcClinical and experimental medicineTargeting SET to counteract Lyn activation demonstrates anti-cancer potential in diffuse large B-cell lymphoma.PMC12578764TPCH-113-37NSTC 114-2811-B-A49A-004V114C-013ABMRD002NSTC 112-2314-B-A49-083-MY3B1131020Chang YYWang WLLiu CYHuang CTChu PYDai MSChen JLfalseTargeting SET to counteract Lyn activation demonstrates anti-cancer potential in diffuse large B-cell lymphoma.Diffuse large B-cell lymphoma (DLBCL) is characterized by molecular complexity and heterogeneity. The SET oncoprotein is overexpressed in B-cell chronic lymphocytic leukemia and non-Hodgkin lymphoma. Acting as an intrinsic inhibitor of the tumor suppressor protein phosphatase 2A (PP2A), targeting SET has shown anti-cancer activity. In this study, we investigated the molecular mechanism of SET antagonism in DLBCL. Overexpression of SET resulted in decreased phosphatase activities of PP2A and SHP-1, while activating Lyn. Conversely, SET inhibition, either through antagonists or siRNA, led to the activation of PP2A and SHP-1, resulting in the inactivation of Lyn. Analysis of public datasets revealed upregulation of Lyn in late-stage DLBCL samples, which was associated with a worse outcome. Ec2025-01-01T00:00:00Z2025 Oct2026-06-06T14:49:21.567Z2026-06-01T03:07:29.997ZS-EPMC125787644117149010.1007/s10238-025-01874-x