دورية أكاديمية
AKT/FOXO signaling enforces reversible differentiation blockade in myeloid leukemias
| العنوان: | AKT/FOXO signaling enforces reversible differentiation blockade in myeloid leukemias |
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| المؤلفون: | Sykes, Stephen M., Lane, Steven W., Bullinger, Lars, Kalaitzidis, Demetrios, Yusuf, Rushdia, Saez, Borja, Ferraro, Francesca, Mercier, Francois, Singh, Harshabad, Brumme, Kristina M., Acharya, Sanket S., Schoell, Claudia, Tothova, Zuzana, Attar, Eyal C., Froehling, Stefan, DePinho, Ronald A., Armstrong, Scott A., Gilliland, D. Gary, Scadden, David T. |
| بيانات النشر: | Cell Press |
| سنة النشر: | 2011 |
| المجموعة: | The University of Queensland: UQ eSpace |
| مصطلحات موضوعية: | Hematopoietic Stem-Cells, Protein-Kinase-B, Forkhead Transcription Factor, Jun Activation Domain, Oxidative Stress, Akt Phosphorylation, Tumor Suppressors, Initiating Cells, Insulin, Foxo |
| الوصف: | 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 0092-8674 1097-4172 |
| العلاقة: | orcid:0000-0002-8050-6209; 5T32HL007623-24; BU 1339/3-1; U01CA141508; HL097794; DK050234 |
| الإتاحة: | https://doi.org/10.1016/j.cell.2011.07.032Test https://espace.library.uq.edu.au/view/UQ:281938Test |
| رقم الانضمام: | edsbas.A0C042D1 |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 00928674 10974172 |
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