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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
5
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pubmed:dateCreated |
2011-9-2
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pubmed:abstractText |
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.
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pubmed:grant |
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pubmed:commentsCorrections |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Sep
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pubmed:issn |
1097-4172
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pubmed:author |
pubmed-author:AcharyaSanket SSS,
pubmed-author:ArmstrongScott ASA,
pubmed-author:AttarEyal CEC,
pubmed-author:BrummeKristina MKM,
pubmed-author:BullingerLarsL,
pubmed-author:DePinhoRonald ARA,
pubmed-author:FerraroFrancescaF,
pubmed-author:FröhlingStefanS,
pubmed-author:GillilandD GaryDG,
pubmed-author:KalaitzidisDemetriosD,
pubmed-author:LaneSteven WSW,
pubmed-author:MercierFrancoisF,
pubmed-author:SaezBorjaB,
pubmed-author:ScaddenDavid TDT,
pubmed-author:SchollClaudiaC,
pubmed-author:SinghHarshabadH,
pubmed-author:SykesStephen MSM,
pubmed-author:TothovaZuzanaZ,
pubmed-author:YusufRushdiaR
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pubmed:copyrightInfo |
Copyright © 2011 Elsevier Inc. All rights reserved.
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pubmed:issnType |
Electronic
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pubmed:day |
2
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pubmed:volume |
146
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
697-708
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pubmed:dateRevised |
2011-11-7
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pubmed:meshHeading |
pubmed-meshheading:21884932-Animals,
pubmed-meshheading:21884932-Antigens, CD34,
pubmed-meshheading:21884932-Apoptosis,
pubmed-meshheading:21884932-Bone Marrow Cells,
pubmed-meshheading:21884932-Cell Differentiation,
pubmed-meshheading:21884932-Cell Line, Tumor,
pubmed-meshheading:21884932-Cells, Cultured,
pubmed-meshheading:21884932-Disease Models, Animal,
pubmed-meshheading:21884932-Forkhead Transcription Factors,
pubmed-meshheading:21884932-Humans,
pubmed-meshheading:21884932-JNK Mitogen-Activated Protein Kinases,
pubmed-meshheading:21884932-Leukemia, Myeloid,
pubmed-meshheading:21884932-Mice,
pubmed-meshheading:21884932-Neoplastic Stem Cells,
pubmed-meshheading:21884932-Proto-Oncogene Proteins c-akt,
pubmed-meshheading:21884932-Signal Transduction
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pubmed:year |
2011
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pubmed:articleTitle |
AKT/FOXO signaling enforces reversible differentiation blockade in myeloid leukemias.
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pubmed:affiliation |
Center for Regenerative Medicine and Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
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