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<p><i>TBL1XR1</i> is frequently mutated in diffuse large B-cell lymphoma (DLBCL), yet its functional impact on tumor microenvironment remains poorly defined. In this study, we characterized <i>TBL1XR1</i> mutations in a cohort of 1842 newly diagnosed DLBCL patients, identifying mutations in 9.4% of cases (<i>n</i> = 173). These mutations correlated with clinically aggressive features, including older age (&gt; 60 years), high-risk International Prognostic Index, enrichment in non-GCB subtypes, as well as inferior progression-free and overall survival. Mechanistically, <i>TBL1XR1</i> mutations enhanced H3K27ac levels at the MYC promoter, increased MYC expression and subsequently up-regulated its immune-regulatory targets CD47 and PD-L1. This axis impaired natural killer (NK) cytotoxicity, facilitating immune escape and tumor progression. In a murine A20 B-lymphoma model, tumors harboring <i>Tbl1xr1</i> mutations exhibited up-regulated MYC, CD47, and PD-L1 expression, resulting in NK cell dysfunction and tumor growth acceleration via the MYC-CD47/PD-L1 axis. Dual blockade of CD47 and PD-L1 restored NK cell-mediated tumor immunity, triggering rapid regression of <i>Tbl1xr1</i>-mutated tumors. Taken together, our findings identified <i>TBL1XR1</i> mutations as a microenvironment-related mechanism of DLBCL progression and provided clinical rationale of co-targeting CD47 and PD-L1 to treat this genetically defined subset.</p>

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TBL1XR1 mutations promoted tumor progression in diffuse large B-cell lymphoma through impairing nature killer cytotoxicity via the MYC-CD47/PD-L1 axis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月11日

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  • Yue Zhu,
  • Yi-Ge Shen,
  • Wei Tang,
  • Zhong Zheng,
  • Si-Yuan Chen,
  • Yao-Hui Huang,
  • Di Fu,
  • Shu Cheng,
  • Peng-Peng Xu,
  • Li Wang,
  • Jiahao Chen,
  • Meng-Meng Ji,
  • Wei-Li Zhao

摘要

TBL1XR1 is frequently mutated in diffuse large B-cell lymphoma (DLBCL), yet its functional impact on tumor microenvironment remains poorly defined. In this study, we characterized TBL1XR1 mutations in a cohort of 1842 newly diagnosed DLBCL patients, identifying mutations in 9.4% of cases (n = 173). These mutations correlated with clinically aggressive features, including older age (> 60 years), high-risk International Prognostic Index, enrichment in non-GCB subtypes, as well as inferior progression-free and overall survival. Mechanistically, TBL1XR1 mutations enhanced H3K27ac levels at the MYC promoter, increased MYC expression and subsequently up-regulated its immune-regulatory targets CD47 and PD-L1. This axis impaired natural killer (NK) cytotoxicity, facilitating immune escape and tumor progression. In a murine A20 B-lymphoma model, tumors harboring Tbl1xr1 mutations exhibited up-regulated MYC, CD47, and PD-L1 expression, resulting in NK cell dysfunction and tumor growth acceleration via the MYC-CD47/PD-L1 axis. Dual blockade of CD47 and PD-L1 restored NK cell-mediated tumor immunity, triggering rapid regression of Tbl1xr1-mutated tumors. Taken together, our findings identified TBL1XR1 mutations as a microenvironment-related mechanism of DLBCL progression and provided clinical rationale of co-targeting CD47 and PD-L1 to treat this genetically defined subset.