Center for Regenerative Medicine and Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
Cell. 2011 Sep 2;146(5):697-708. doi: 10.1016/j.cell.2011.07.032.
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.
AKT 的激活与许多恶性肿瘤有关，AKT 的作用部分是通过抑制 FOXO 肿瘤抑制因子。我们在急性髓细胞白血病 (AML) 中发现了 AKT/FOXO 的相反作用。我们观察到，在 AML 患者样本中，大约 40%的 FOXO 是活跃的，而不管遗传亚型如何。我们还在人类 MLL-AF9 白血病诱导的 AML 小鼠中观察到这种活性，其中 Akt 的激活或 FoxO1/3/4 的复合缺失减少了白血病细胞的生长，后者显著降低了体内白血病起始细胞 (LIC) 的功能并改善了动物的存活率。FOXO 抑制导致髓样成熟和随后的 AML 细胞死亡。FOXO 的激活与 JNK/c-JUN 信号呈负相关，对 FOXO 抑制有抗性的白血病细胞对 JNK 抑制有反应。这些数据揭示了 AKT/FOXO 和 JNK/c-JUN 在维持分化阻断中的分子作用，这种阻断可以针对具有多种遗传病变的白血病进行靶向抑制。
