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首页> 外文期刊>Cell cycle >The role of the PTEN/AKT Pathway in NOTCH1-induced leukemia.
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The role of the PTEN/AKT Pathway in NOTCH1-induced leukemia.

机译：PTEN / AKT途径在NOTCH1诱导的白血病中的作用。

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摘要

Activating mutations in NOTCH1 are the most prominent genetic abnormality in T-cell acute Lymphoblastic Leukemia (T-ALL) and inhibition of NOTCH1 signaling with gamma-secretase inhibitors (GSIs) has been proposed as targeted therapy in this disease. However, most T-ALL cell lines with mutations in NOTCH1 fail to respond to GSI therapy. Using gene expression profiling and mutation analysis we showed that mutational loss of PTEN is a common event in T-ALL and is associated with resistance to NOTCH inhibition. Furthermore, our studies revealed that NOTCH1 induces upregulation of the PI3K-AKT pathway via HES1, which negatively controls the expression of PTEN. This regulatory circuitry is evolutionary conserved from Drosophila to humans as demonstrated by the interaction of overexpression of Delta and Akt in a model of Notch-induced transformation in the fly eye. Loss of PTEN and constitutive activation of AKT in T-ALL induce increased glucose metabolism and bypass the requirement of NOTCH1 signaling to sustain cell growth. Importantly, PTEN-null/GSI resistant T-ALL cells switch their oncogene addiction from NOTCH1 to AKT and are highly sensitive to AKT inhibitors. These results should facilitate the development of molecular therapies targeting NOTCH1 and AKT for the treatment of T-ALL.
机译：NOTCH1的激活突变是T细胞急性淋巴细胞白血病（T-ALL）中最突出的遗传异常，并且有人提出用γ-分泌酶抑制剂（GSIs）抑制NOTCH1信号传导是该疾病的靶向治疗方法。但是，大多数在NOTCH1中发生突变的T-ALL细胞系对GSI治疗均无反应。使用基因表达谱和突变分析，我们发现PTEN的突变丢失是T-ALL中的常见事件，并且与对NOTCH抑制的抗性相关。此外，我们的研究表明，NOTCH1通过HES1诱导PI3K-AKT通路的上调，从而负面控制PTEN的表达。这种调节电路是从果蝇到人类的进化保守性，这是通过在Notch诱导的蝇眼转化模型中Delta和Akt的过表达相互作用来证明的。 T-ALL中PTEN的丢失和AKT的组成性激活会诱导葡萄糖代谢增加，并绕过NOTCH1信号传导维持细胞生长的需要。重要的是，耐PTEN无效/ GSI的T-ALL细胞将其癌基因成瘾从NOTCH1转换为AKT，并对AKT抑制剂高度敏感。这些结果应该促进针对NOTCH1和AKT的分子疗法的发展，以治疗T-ALL。

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