AKT/FOXO Signaling Enforces Reversible Differentiation Blockade in Myeloid Leukemias

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• 作者：Stephen  ; M. Sykes¹ ;   ; ² ; Steven  ; W. Lane³ ;   ; ⁸ ; Lars Bullinger⁶ ; Demetrios Kalaitzidis³ ; Rushdia Yusuf¹ ;   ; ² ; Borja Saez¹ ;   ; ² ; Francesca Ferraro¹ ;   ; ² ; Francois Mercier¹ ;   ; ² ; Harshabad Singh¹ ; Kristina  ; M. Brumme³ ; Sanket  ; S. Acharya¹ ;   ; ² ; Claudia Scholl⁶ ; Zuzana Tothova⁴ ; Eyal  ; C. Attar¹ ; Stefan Frö ; hling⁶ ; Ronald  ; A. DePinho⁵ ;   ; ⁹ ; D.  ; Gary Gilliland⁷ ; Scott  ; A. Armstrong³ ; David  ; T. Scadden¹ ;   ; ² ;   ; ^{dscadden@mgh.harvard.edu}
• 刊名：Cell
• 出版年：2011
• 出版时间：2 September 2011
• 年：2011
• 卷：146
• 期：5
• 页码：697-708
• 全文大小：1539 K

文摘

Summary

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 ?0 % 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.

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