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Constitutive Activation of Akt by Flt3 Internal Tandem Duplications Is Necessary for Increased Survival, Proliferation, and Myeloid Transformation

¹ Department of Medicine, Hematology and Oncology; ² Interdisciplinary Center for Clinical Research; and ³ Institute of Pathology, University of Münster, Münster, Germany and ⁴ Comprehensive Cancer Center and Cancer Research Institute, University of California, San Francisco, California

Requests for reprints: Christian Brandts, Department of Medicine, Hematology and Oncology, University of Münster, Albert-Schweitzer-Strasse 33, D-48129 Münster, Germany. Phone: 49-251-83-52490; Fax: 49-251-83-52673; E-mail: cbrandts{at}uni-muenster.de.

Up to 30% of patients with acute myeloid leukemia (AML) harbor internal tandem duplications (ITD) within the FLT3 gene, encoding a receptor tyrosine kinase. These mutations induce constitutive tyrosine kinase activity in the absence of the natural Flt3 ligand and confer growth factor independence, increased proliferation, and survival to myeloid precursor cells. The signaling pathways and downstream nuclear targets mediating leukemic transformation are only partly identified. Here, we show that the presence of Flt3-ITD constitutively activates Akt (PKB), a key serine-threonine kinase within the phosphatidylinositol 3-kinase pathway. Constitutive activation of Akt phosphorylated and inhibited the transcription factor Foxo3a. Restored Foxo3a activity reversed Flt3-ITD–mediated growth properties and dominant-negative Akt prevented Flt3-ITD–mediated cytokine independence. Conditional Akt activation targeted to the cell membrane induced cytokine-independent survival, cell cycle progression, and proliferation. Importantly, Akt activation was sufficient to cause in vitro transformation of 32D myeloid progenitor cells and in vivo promoted the development of a leukemia-like myeloid disease. Akt phosphorylation was found in myeloid blasts of 86% of AML patients, suggesting an important role in leukemogenesis. In summary, Akt is necessary for increased survival, proliferation, and leukemic transformation by Flt3-ITD, possibly by inactivation of Foxo transcription factors. These findings indicate that Akt and Foxo transcription factors are attractive targets for therapeutic intervention in AML.

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