Abstract The MYC oncogene drives the pathogenesis of many hematopoietic malignancies, including Burkitt’s lymphoma (BL) and Acute Lymphoblastic Leukemia (ALL). These malignancies are often “oncogene-addicted” to MYC. Using mass cytometry (CyTOF), we demonstrate that MYC-addicted T-ALL excludes specific immune subsets from the tumor microenvironment implicated in immune surveillance, including natural killer (NK) cells. MYC inhibition clears malignant lymphocytes from the spleen and restores the normal splenic NK composition. Concordantly, peripheral blood of T-ALL patients have reduced percentages of activated NK cells as compared to healthy individuals. We show that MYC excludes activated NK cells from sites of lymphomagenesis by suppressing ERK1/2-STAT1/2-Type I IFN signaling, in both murine and human lymphomas. Furthermore, MYC-associated BL patients with higher than median expression of STAT1/2, and cytotoxic NK cell genes, PRF1 and Granzymes, have favorable clinical outcomes. Hence, oncogenic MYC appears to causally and reversibly suppress NK-mediated immune surveillance during lymphomagenesis. Citation Format: Srividya Swaminathan, Adriane Mosley, Crista Horton, Daniel F. Liefwalker, Anja Deutzmann, Renumathy Dhanasekaran, Arvin Gouw, Andrew Gentles, Martin Eilers, Holden T. Maecker, Dean W. Felsher. MYC functions as a master switch for natural killer cell-mediated immune surveillance of lymphoid malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2943. doi:10.1158/1538-7445.AM2017-2943