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). Using CyTOF, we demonstrate a systemic reduction in natural killer (NK) cell-mediated surveillance in SRα-tTA/Tet-O-MYC ON mice bearing MYC-driven T-lymphomas, due to an arrest in NK cell maturation. Inactivation of lymphoma-intrinsic MYC releases the brakes on NK maturation restoring NK homeostasis. 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. 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. Adoptive transfer of mature NK cells is sufficient to delay both T-lymphoma growth and recurrence post MYC inactivation. Our studies thus provide a rationale for developing NK cell-based therapies to effectively treat MYC-driven lymphomas in the future. Abbreviations: CyTOF Cytometry Time of Flight BL Burkitt’s Lymphoma ALL Acute Lymphoblastic Leukemia DLBCL Diffuse Large B Cell Lymphoma NK Cell Natural Killer Cell STAT1/2 Signal Transducer and Activator of Transcription 1/2 IFN Interferon DC Dendritic Cell MYC v-myc avian myelocytomatosis viral oncogene homolog PRECOG Prediction of Clinical Outcomes from Genomic Profiles BLI Bioluminescence Imaging TSS Transcriptional Start Site HTLV Human T-lymphotropic Virus hMYC human MYC