Abstract

The MYC oncogene drives T and B lymphoid malignancies, including Burkitts lymphoma (BL) and Acute Lymphoblastic Leukemia (ALL). Using CyTOF, we demonstrate a systemic reduction in natural killer (NK) cell-mediated surveillance in SR-tTA/Tet-O-MYCON 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.\n\nAbbreviations