AKT/FOXO signaling enforces reversible differentiation blockade in myeloid leukemias.
AKT/FOXO signaling enforces reversible differentiation blockade in myeloid leukemias.
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DOI：
10.1016/j.cell.2011.07.032
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发表时间：
2011-09-02
期刊：
影响因子：
64.5
通讯作者：
Scadden DT
中科院分区：
文献类型：
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作者：
Sykes SM;Lane SW;Bullinger L;Kalaitzidis D;Yusuf R;Saez B;Ferraro F;Mercier F;Singh H;Brumme KM;Acharya SS;Scholl C;Tothova Z;Attar EC;Fröhling S;DePinho RA;Armstrong SA;Gilliland DG;Scadden DT
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。我们发现AKT/FOXO在急性髓系白血病(AML)中的作用相反。我们观察到，FOXO在40%的急性髓细胞白血病患者样本中是活跃的，而不是降低FOXO活性，而不是遗传亚型。我们在人类MLL-AF9白血病等位基因诱导的小鼠AML中也观察到了这种活性，Akt的激活或FoxO1/3/4的复合缺失都会抑制白血病细胞的生长，后者显著降低体内的白血病启动细胞(LIC)功能，并提高动物的存活率。FOXO抑制可导致髓系成熟和随后的AML细胞死亡。FOXO激活与JNK/c-Jun信号转导负相关，对FOXO抑制耐药的白血病细胞对JNK抑制有反应。这些数据揭示了AKT/FOXO和JNK/c-Jun在维持分化阻断方面的分子作用，该分化阻断可以靶向抑制具有一系列遗传损害的白血病。
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.
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