Constitutive activation of Akt kinases is necessary for the survival and proliferation of a number of types of cancer cells, and has been shown to play an important role in transformantion by Abl oncoproteins. Although the products of the three Akt genes are very similar and have identical activities, individual genes may have different roles in both normal physiology and cancer progression. To assess the roles of these genes in Abl-mediated transformation, the ability of v-Abl to transform bone marrow cells from Akt 1-/-, Akt 2-/-, Akt 3-/- or Akt2/3-/- mice were compared. In all cases, primary transformation kinetics and establishment of transformants from null animals was similar to that observed with bone marrow from wild type littermate controls. However, an essential role for Akt in Abl-mediated transformation was revealed when the Cre recombinase was used to delete the floxed akt1 gene in transformants from akt 2/akt 3-/- mice. Loss of all Akt genes blocked cell growth. Consistent with these data, RT-PCR analyses of Akt expression in transformants revealed that all three Akt genes are expressed. However, analyses of the normal pre-B cell population that comprises the major target cell of transformation, B220+ CD43+ bone marrow cells, revealed that this population expresses only the Akt2 gene. Additional analyses using temperature-sensitive Abl-transformed cells and imatinib, an inhibitor of Abl kinases, revealed that all three Akt genes are induced in the presence of an active Abl protein. These data reveal Akt as a previously unappreciated target of activation by Abl proteins and suggest that Akt may be an attractive molecule for intervention in Abl-mediated leukemias.
[Proc Amer Assoc Cancer Res, Volume 47, 2006]