The phosphatidylinositol 3-kinase/AKT pathway is an integral component of signaling involved in the development of many cancers, including myeloid leukemias such as chronic myeloid leukemia and acute myeloid leukemia (AML). Increased AKT1 activity is frequently seen in AML patients, providing leukemic cells with growth and survival promoting signals. An important aspect of AKT1 function is its involvement in cellular metabolism and energy production. Under some circumstances, strong activation of AKT1 increases oxidative stress, which can cause apoptosis when cells progressively build up excess free radicals. This has been described in hematopoietic cells overexpressing activated AKT1; however, whether this is true in cells coexpressing other genetic events involved in leukemia is not known. This prompted us to investigate the effect of constitutively active AKT1 (myristoylated AKT1) in hematopoietic progenitor cells expressing constitutively active signal transducer and activator of transcription 5, Fms-related tyrosine kinase 3-internal tandem duplication, or antiapoptotic B-cell lymphoma 2. Surprisingly, myristoylated AKT1 was incompatible with proliferation driven by both signal transducer and activator of transcription 5 and Fms-related tyrosine kinase 3-internal tandem duplication, which triggered cell cycle block and apoptosis. Moreover, transplantable cells of B-cell lymphoma 2-transgenic mice were impaired in their engraftment ability to recipient mice when expressing hyperactivated AKT1. This Was linked to AKT1-mediated proapoptotic functions and not to impairment in homing to the bone marrow. Although cells expressing hyperactivated AKT1 displayed higher levels of reactive oxygen species both in vitro and in vivo, the addition of the antioxidant N-acetyl-L-cysteine significantly reduced apoptosis. Taken together, the results indicate that constitutive AKT1 activity is incompatible with growth- and survival-promoting ability of other activated genes in AML. Copyright (C) 2015 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc.