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BCR-ABL Regulates Phosphatidylinositol 3-Kinase-p110γ Transcription and Activation and Is Required for Proliferation and Drug Resistance*

The BCR-ABL oncogene is the hallmark of chronic myeloid leukemia, a clonal hematopoietic stem cell disorder. BCR-ABL displays constitutive tyrosine kinase activity, required for its transformation ability. Although the molecular mechanisms behind this malignancy are not fully understood, a role for phosphatidylinositol (PI) 3-kinase has been repeatedly described. Here we report the specific up-regulation of the class IB catalytic subunit of PI 3-kinase (p110γ) in response to BCR-ABL expression. We demonstrate that this upregulation is due to increased transcription and is dependent on both PI 3-kinase and MEK activity. We performed in vitro kinase activity assays and show that BCR-ABL also leads to increased p110γ activity and that this activation requires both G protein-coupled receptor and Ras signaling. In addition, by transfection of cells with dominant negative p110γ, we determined that this specific PI 3-kinase isoform is involved in both proliferation and the apoptosis resistance associated with chronic myeloid leukemia. The data presented here define for the first time the ability of BCR-ABL to alter the expression levels of PI 3-kinase isoforms and also demonstrate a previously unreported link between BCR-ABL and p110γ.