Notch signaling pathway activation is known to contribute to the pathogenesis of 
a spectrum of human malignancies, including T cell leukemia. However, recent 
studies have implicated the Notch pathway as a tumor suppressor in 
myeloproliferative neoplasms and several solid tumors. Here we report a novel 
tumor suppressor role for Notch signaling in acute myeloid leukemia (AML) and 
demonstrate that Notch pathway activation could represent a therapeutic strategy 
in this disease. We show that Notch signaling is silenced in human AML samples, 
as well as in AML-initiating cells in an animal model of the disease. In vivo 
activation of Notch signaling using genetic Notch gain of function models or in 
vitro using synthetic Notch ligand induces rapid cell cycle arrest, 
differentiation, and apoptosis of AML-initiating cells. Moreover, we demonstrate 
that Notch inactivation cooperates in vivo with loss of the myeloid tumor 
suppressor Tet2 to induce AML-like disease. These data demonstrate a novel tumor 
suppressor role for Notch signaling in AML and elucidate the potential 
therapeutic use of Notch receptor agonists in the treatment of this devastating 
leukemia.