N-MYC regulates Cell Survival via eIF4G1 in inv(16) Acute Myeloid Leukemia

c-MYC and N-MYC are critical regulators of hematopoietic stem cell activity. While the role of c-MYC deregulation is studied in detail in hematological malignancies, the importance of N-MYC deregulation in leukemogenesis remains elusive. Here we demonstrate that N-MYC is overexpressed in acute myeloid leukemia (AML) cells with chromosome inversion inv(16) and crucial to the survival and maintenance of inv(16) leukemia. We identified a novel MYCN enhancer, active in multiple AML subtypes, essential for MYCN mRNA levels and survival in inv(16) AML cells. We also identified eukaryotic translation initiation factor 4 gamma 1 (eIF4G1) as a key N-MYC target that sustains leukemic survival in inv(16) AML cells. Ours is the first report to demonstrate the oncogenic role of eIF4G1 in AML. Our results reveal a mechanism whereby N-MYC drives a leukemic transcriptional program and provide a rationale for the therapeutic targeting of the N-MYC/eIF4G1 axis in myeloid leukemia.