AKT/FOXO signaling enforces reversible differentiation blockade in myeloid leukemias

Stephen M. Sykes, Steven W. Lane, Lars Bullinger, Demetrios Kalaitzidis, Rushdia Yusuf, Borja Saez, Francesca Ferraro, Francois Mercier, Harshabad Singh, Kristina M. Brumme, Sanket S. Acharya, Claudia Schöll, Zuzana Tothova, Eyal C. Attar, Stefan Fröhling, Ronald A. Depinho, Scott A. Armstrong, D. Gary Gilliland, David T. Scadden

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174 Scopus citations

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. PaperClip:

Original languageEnglish
Pages (from-to)697-708
Number of pages12
JournalCell
Volume146
Issue number5
DOIs
StatePublished - Sep 2 2011
Externally publishedYes

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    Sykes, S. M., Lane, S. W., Bullinger, L., Kalaitzidis, D., Yusuf, R., Saez, B., Ferraro, F., Mercier, F., Singh, H., Brumme, K. M., Acharya, S. S., Schöll, C., Tothova, Z., Attar, E. C., Fröhling, S., Depinho, R. A., Armstrong, S. A., Gilliland, D. G., & Scadden, D. T. (2011). AKT/FOXO signaling enforces reversible differentiation blockade in myeloid leukemias. Cell, 146(5), 697-708. https://doi.org/10.1016/j.cell.2011.07.032