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

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-MYC mice bearing MYC-driven T-lymphomas. Residual mNK cells in spleen...

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Bibliographic Details
Published in:	Nature communications 2020-06, Vol.11 (1), p.2860-2860, Article 2860
Main Authors:	Swaminathan, Srividya, Hansen, Aida S, Heftdal, Line D, Dhanasekaran, Renumathy, Deutzmann, Anja, Fernandez, Wadie D M, Liefwalker, Daniel F, Horton, Crista, Mosley, Adriane, Liebersbach, Mariola, Maecker, Holden T, Felsher, Dean W
Format:	Article
Language:	eng
Subjects:	Acute lymphoblastic leukemia Addiction Adoptive Transfer Animals Bearing Burkitt Lymphoma - immunology Burkitt Lymphoma - mortality Burkitt's lymphoma Cell Line, Tumor - transplantation Cell survival Deactivation Disease Models, Animal Gene Expression Regulation, Neoplastic - immunology Humans Immune system Immunologic Surveillance - genetics Immunosurveillance Inactivation Interferon Interferon Type I - pharmacology Interferon Type I - therapeutic use Killer Cells, Natural - drug effects Killer Cells, Natural - immunology Killer Cells, Natural - transplantation Leukemia Lymphatic leukemia Lymphoma Lymphoma, T-Cell - drug therapy Lymphoma, T-Cell - genetics Lymphoma, T-Cell - immunology Lymphoma, T-Cell - pathology Male Maturation Mice Myc protein Natural killer cells Primary Cell Culture Proto-Oncogene Proteins c-myc - genetics Proto-Oncogene Proteins c-myc - metabolism Signal Transduction - drug effects Signal Transduction - genetics Signal Transduction - immunology Stat1 protein STAT1 Transcription Factor - metabolism Stat2 protein STAT2 Transcription Factor - metabolism Transcription
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Summary:	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-MYC mice bearing MYC-driven T-lymphomas. Residual mNK cells in spleens of MYC 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.
ISSN:	2041-1723 2041-1723