Oncogenic E17K mutation in the pleckstrin homology domain of AKT1 promotes v-Abl-mediated pre-B-cell transformation and survival of Pim-deficient cells.

Abl-mediated transformation requires the activation of multiple pathways involved in the cellular proliferation and survival, including PI3K/AKT and JAK/STAT-dependent Pim kinases. Recently, the E17K mutation in the AKT1 has been associated with multiple human malignancies and leukemia in mice. However, this mutation has not been identified in Abl-transformed cells. We investigated the presence of the AKT1(E17K) mutation in v-Abl-transformed cell clones. AKT1(E17K) was detected in 3 (2.6%) of 116 specimens examined. To show the involvement of AKT1(E17K) directly in v-Abl-mediated tumorigenesis, we infected bone marrow cells from mice with bicistronic retroviruses encoding v-Abl and either wild-type or the mutant AKT1. Interestingly, we found that E17K mutant greatly increased the v-Abl transformation efficiency as compared with wild-type AKT1. Ectopic expression of E17K mutant increased the expression levels of antiapoptotic protein BCL2 and phosphorylation levels of proapoptotic protein BAD. This correlated with an increased protection from imatinib-induced apoptosis in Abl transformants. Furthermore, AKT1(E17K) promotes survival of the Pim-deficient cells, indicating a functional link between AKT and Pim in v-Abl transformation. In addition, AKT1(E17K) delays loss of Pim-1 and Pim-2 protein levels on v-Abl inactivation, which suggests that there exists reciprocal signaling between AKT and Pim in v-Abl transformants.