Targeting 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. Ectopic expression of Lyn enhanced the cell viability and migratory capacity of DLBCL cells. Notably, Lyn inhibited PP2A and SHP-1 phosphatase activities, suggesting the existence of a SET/PP2A/SHP-1/Lyn feedback loop. Immunohistochemically, SHP-1 levels were negatively correlated with pLyn/Lyn levels in DLBCL tissues. Overall, these results suggest that SET antagonism to inactivate Lyn represents an attractive approach for DLBCL treatment.