AKT/FOXO signaling enforces reversible differentiation blockade in myeloid leukemias

Sykes, Stephen M., Lane, Steven W., Bullinger, Lars, Kalaitzidis, Demetrios, Yusuf, Rushdia, Saez, Borja, Ferraro, Francesca, Mercier, Francois, Singh, Harshabad, Brumme, Kristina M., Acharya, Sanket S., Schoell, Claudia, Tothova, Zuzana, Attar, Eyal C., Froehling, Stefan, DePinho, Ronald A., Armstrong, Scott A., Gilliland, D. Gary and Scadden, David T. (2011) AKT/FOXO signaling enforces reversible differentiation blockade in myeloid leukemias. Cell, 146 5: 697-708. doi:10.1016/j.cell.2011.07.032

Author Sykes, Stephen M.
Lane, Steven W.
Bullinger, Lars
Kalaitzidis, Demetrios
Yusuf, Rushdia
Saez, Borja
Ferraro, Francesca
Mercier, Francois
Singh, Harshabad
Brumme, Kristina M.
Acharya, Sanket S.
Schoell, Claudia
Tothova, Zuzana
Attar, Eyal C.
Froehling, Stefan
DePinho, Ronald A.
Armstrong, Scott A.
Gilliland, D. Gary
Scadden, David T.
Title AKT/FOXO signaling enforces reversible differentiation blockade in myeloid leukemias
Journal name Cell   Check publisher's open access policy
ISSN 0092-8674
Publication date 2011-09
Sub-type Article (original research)
DOI 10.1016/j.cell.2011.07.032
Volume 146
Issue 5
Start page 697
End page 708
Total pages 12
Place of publication Cambridge, MA, United States
Publisher Cell Press
Language eng
Formatted 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.
Keyword Hematopoietic Stem-Cells
Forkhead Transcription Factor
Jun Activation Domain
Oxidative Stress
Akt Phosphorylation
Tumor Suppressors
Initiating Cells
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Medicine Publications
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 105 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 109 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Fri, 14 Sep 2012, 19:11:04 EST by System User on behalf of School of Medicine