| First Author | Sykes SM | Year | 2011 |
| Journal | Cell | Volume | 146 |
| Issue | 5 | Pages | 697-708 |
| PubMed ID | 21884932 | Mgi Jnum | J:176214 |
| Mgi Id | MGI:5289720 | Doi | 10.1016/j.cell.2011.07.032 |
| Citation | Sykes SM, et al. (2011) AKT/FOXO Signaling Enforces Reversible Differentiation Blockade in Myeloid Leukemias. Cell 146(5):697-708 |
| 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 approximately 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. PAPERCLIP: |
