1. AKT/FOXO signaling enforces reversible differentiation blockade in myeloid leukemias.
- Author
-
Sykes SM, Lane SW, Bullinger L, Kalaitzidis D, Yusuf R, Saez B, Ferraro F, Mercier F, Singh H, Brumme KM, Acharya SS, Scholl C, Tothova Z, Attar EC, Fröhling S, DePinho RA, Armstrong SA, Gilliland DG, and Scadden DT
- Subjects
- Animals, Antigens, CD34 metabolism, Apoptosis, Bone Marrow Cells cytology, Bone Marrow Cells metabolism, Cell Differentiation, Cell Line, Tumor, Cells, Cultured, Disease Models, Animal, Forkhead Box Protein O3, Humans, JNK Mitogen-Activated Protein Kinases metabolism, Mice, Neoplastic Stem Cells cytology, Neoplastic Stem Cells metabolism, Forkhead Transcription Factors metabolism, Leukemia, Myeloid metabolism, Leukemia, Myeloid pathology, Proto-Oncogene Proteins c-akt metabolism, Signal Transduction
- 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., (Copyright © 2011 Elsevier Inc. All rights reserved.)
- Published
- 2011
- Full Text
- View/download PDF