Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia
Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia
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DOI：
10.1038/nm1636
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发表时间：
2007-10-01
期刊：
影响因子：
82.9
通讯作者：
Ferrando, Adolfo A.
中科院分区：
文献类型：
--
作者：
Palomero, Teresa;Sulis, Maria Luisa;Ferrando, Adolfo A.
NOTCH1的功能获得突变在T细胞淋巴母细胞性白血病和淋巴瘤(T-ALL)中很常见，这使该受体成为伽马分泌酶抑制剂等药物的有希望的靶点，后者可以阻断NOTCH1激活所需的蛋白水解性切割。然而，由于肿瘤耐药性和关于致癌NOTCH1调控的致癌计划的信息匮乏，人们对这些疗法的热情有所减弱。在这里，我们发现NOTCH1调节正常和白血病T细胞中PTEN(编码磷酸酶和张力蛋白同源物)的表达和磷酸肌醇-3激酶(PI3K)-AKT信号通路的活性。在Notch诱导的果蝇肿瘤发生模型中，Notch信号和PI3K-AKT通路在体内协同作用，PTEN的突变缺失与人类T-ALL对NOTCH1的药理抑制有关。总体而言，这些发现确认PTEN的转录控制和PI3K-AKT通路的调节是NOTCH1激活的白血病程序的关键要素，并为T-ALL的新治疗策略的设计提供了基础。
Gain-of-function mutations in NOTCH1 are common in T- cell lymphoblastic leukemias and lymphomas ( T- ALL), making this receptor a promising target for drugs such as gamma-secretase inhibitors, which block a proteolytic cleavage required for NOTCH1 activation. However, the enthusiasm for these therapies has been tempered by tumor resistance and the paucity of information on the oncogenic programs regulated by oncogenic NOTCH1. Here we show that NOTCH1 regulates the expression of PTEN ( encoding phosphatase and tensin homolog) and the activity of the phosphoinositol- 3 kinase ( PI3K)-AKT signaling pathway in normal and leukemic T cells. Notch signaling and the PI3K-AKT pathway synergize in vivo in a Drosophila melanogaster model of Notch- induced tumorigenesis, and mutational loss of PTEN is associated with human T- ALL resistance to pharmacological inhibition of NOTCH1. Overall, these findings identify transcriptional control of PTEN and regulation of the PI3K-AKT pathway as key elements of the leukemogenic program activated by NOTCH1 and provide the basis for the design of new therapeutic strategies for T- ALL.