title: AKT/FOXO signaling enforces reversible differentiation blockade in myeloid leukemias.
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.
authors: Center for Regenerative Medicine and Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
authors: Stephen M
authors: SM
authors: Sykes
authors: Steven W
authors: SW
authors: Lane
authors: Lars
authors: L
authors: Bullinger
authors: Demetrios
authors: D
authors: Kalaitzidis
authors: Rushdia
authors: R
authors: Yusuf
authors: Borja
authors: B
authors: Saez
authors: Francesca
authors: F
authors: Ferraro
authors: Francois
authors: F
authors: Mercier
authors: Harshabad
authors: H
authors: Singh
authors: Kristina M
authors: KM
authors: Brumme
authors: Sanket S
authors: SS
authors: Acharya
authors: Claudia
authors: C
authors: Scholl
authors: Claudia
authors: C
authors: Schöll
authors: Zuzana
authors: Z
authors: Tothova
authors: Eyal C
authors: EC
authors: Attar
authors: Stefan
authors: S
authors: Fröhling
authors: Ronald A
authors: RA
authors: DePinho
authors: Scott A
authors: SA
authors: Armstrong
authors: D Gary
authors: DG
authors: Gilliland
authors: David T
authors: DT
authors: Scadden
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004195:Disease Models, Animal; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007951:Leukemia, Myeloid / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D018952:Antigens, CD34; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases