期刊
CELL
卷 146, 期 5, 页码 697-708出版社
CELL PRESS
DOI: 10.1016/j.cell.2011.07.032
关键词
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资金
- NHLBI [5T32HL007623-24, U01HL100402]
- Deutsche Forschungsgemeinschaft [BU 1339/3-1]
- Leukemia and Lymphoma Society
- Alex Lemonade Stand Foundation
- Chamber of Industry and Commerce of the Government of Spain
- NCI [U01CA141508, CA140575]
- NIH NHLBI [HL097794, HL097748, HL100402]
- NIDDK [DK050234]
- Ellison Foundation
- Harvard Stem Cell Institute
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 similar to 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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