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MYC functions as a switch for natural killer cell-mediated immune surveillance of lymphoid malignancies

Author

Listed:
  • Srividya Swaminathan

    (Stanford University
    Beckman Research Institute of City of Hope)

  • Aida S. Hansen

    (Stanford University)

  • Line D. Heftdal

    (Stanford University)

  • Renumathy Dhanasekaran

    (Stanford University
    Stanford University)

  • Anja Deutzmann

    (Stanford University)

  • Wadie D. M. Fernandez

    (Stanford University)

  • Daniel F. Liefwalker

    (Stanford University)

  • Crista Horton

    (Stanford University)

  • Adriane Mosley

    (Stanford University)

  • Mariola Liebersbach

    (Stanford University)

  • Holden T. Maecker

    (Stanford University School of Medicine)

  • Dean W. Felsher

    (Stanford University)

Abstract

The MYC oncogene drives T- and B- lymphoid malignancies, including Burkitt’s lymphoma (BL) and Acute Lymphoblastic Leukemia (ALL). Here, we demonstrate a systemic reduction in natural killer (NK) cell numbers in SRα-tTA/Tet-O-MYCON mice bearing MYC-driven T-lymphomas. Residual mNK cells in spleens of MYCON T-lymphoma-bearing mice exhibit perturbations in the terminal NK effector differentiation pathway. Lymphoma-intrinsic MYC arrests NK maturation by transcriptionally repressing STAT1/2 and secretion of Type I Interferons (IFNs). Treating T-lymphoma-bearing mice with Type I IFN improves survival by rescuing NK cell maturation. Adoptive transfer of mature NK cells is sufficient to delay both T-lymphoma growth and recurrence post MYC inactivation. In MYC-driven BL patients, low expression of both STAT1 and STAT2 correlates significantly with the absence of activated NK cells and predicts unfavorable clinical outcomes. Our studies thus provide a rationale for developing NK cell-based therapies to effectively treat MYC-driven lymphomas in the future.

Suggested Citation

  • Srividya Swaminathan & Aida S. Hansen & Line D. Heftdal & Renumathy Dhanasekaran & Anja Deutzmann & Wadie D. M. Fernandez & Daniel F. Liefwalker & Crista Horton & Adriane Mosley & Mariola Liebersbach , 2020. "MYC functions as a switch for natural killer cell-mediated immune surveillance of lymphoid malignancies," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16447-7
    DOI: 10.1038/s41467-020-16447-7
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    Cited by:

    1. Yuxiu Xu & Xin Li & Fang Cheng & Bao Zhao & Min Fang & Zihai Li & Songdong Meng, 2024. "Heat shock protein gp96 drives natural killer cell maturation and anti-tumor immunity by counteracting Trim28 to stabilize Eomes," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    2. Anja Deutzmann & Delaney K. Sullivan & Renumathy Dhanasekaran & Wei Li & Xinyu Chen & Ling Tong & Wadie D. Mahauad-Fernandez & John Bell & Adriane Mosley & Angela N. Koehler & Yulin Li & Dean W. Felsh, 2024. "Nuclear to cytoplasmic transport is a druggable dependency in MYC-driven hepatocellular carcinoma," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    3. Yejinpeng Wang & Lingao Ju & Gang Wang & Kaiyu Qian & Wan Jin & Mingxing Li & Jingtian Yu & Yiliang Shi & Yongzhi Wang & Yi Zhang & Yu Xiao & Xinghuan Wang, 2023. "DNA polymerase POLD1 promotes proliferation and metastasis of bladder cancer by stabilizing MYC," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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