Author/Authors :
Stephen M. Sykes، نويسنده , , Steven W. Lane، نويسنده , , Lars Bullinger، نويسنده , , Demetrios Kalaitzidis، نويسنده , , Rushdia Yusuf، نويسنده , , Borja Saez، نويسنده , , Francesca Ferraro، نويسنده , , Francois Mercier، نويسنده , , Harshabad Singh، نويسنده , , Kristina M. Brumme، نويسنده , , Sanket S. Acharya، نويسنده , , Claudia Scholl، نويسنده , , Zuzana Tothova، نويسنده , , Eyal C. Attar، نويسنده , , Stefan Fr?hling، نويسنده , , Ronald A. DePinho، نويسنده , , D. Gary Gilliland، نويسنده , , Scott A. Armstrong، نويسنده , , David T. Scadden، نويسنده ,
Abstract :
AKT activation is associated with many malignancies, where AKT acts, in part, by inhibiting FOXO tumor suppressors. We show a converse role for AKT/FOXOs in acute myeloid leukemia (AML). Rather than decreased FOXO activity, we observed that FOXOs are active in ∼40% of AML patient samples regardless of genetic subtype. We also observe this activity in human MLL-AF9 leukemia allele-induced AML in mice, where either activation of Akt or compound deletion of FoxO1/3/4 reduced leukemic cell growth, with the latter markedly diminishing leukemia-initiating cell (LIC) function in vivo and improving animal survival. FOXO inhibition resulted in myeloid maturation and subsequent AML cell death. FOXO activation inversely correlated with JNK/c-JUN signaling, and leukemic cells resistant to FOXO inhibition responded to JNK inhibition. These data reveal a molecular role for AKT/FOXO and JNK/c-JUN in maintaining a differentiation blockade that can be targeted to inhibit leukemias with a range of genetic lesions.
