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<p>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.</p>

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Targeting SET to counteract Lyn activation demonstrates anti-cancer potential in diffuse large B-cell lymphoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月31日

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  • Ji-Lin Chen,
  • Pei-Yi Chu,
  • Chun-Teng Huang,
  • Wan-Lun Wang,
  • Yuan-Ya Chang,
  • Ming-Shen Dai,
  • Chun-Yu Liu

摘要

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.