Display Settings:

Format

Send to:

Choose Destination
See comment in PubMed Commons below
Cell. 2011 Sep 2;146(5):697-708. doi: 10.1016/j.cell.2011.07.032.

AKT/FOXO signaling enforces reversible differentiation blockade in myeloid leukemias.

Author information

  • 1Center for Regenerative Medicine and Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.

Erratum in

  • Cell. 2011 Sep 30;147(1):247. Schöll, Claudia [corrected to Scholl, Claudia].

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.

Comment in

PMID:
21884932
[PubMed - indexed for MEDLINE]
PMCID:
PMC3826540
Free PMC Article

Images from this publication.See all images (7)Free text

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Elsevier Science Icon for PubMed Central
    Loading ...
    Write to the Help Desk