PTEN opposes negative selection and enables oncogenic transformation of pre-B cells.
PTEN opposes negative selection and enables oncogenic transformation of pre-B cells.
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PTEN是PI3K-AKT信号的负调控因子，在许多类型的癌症中具有强大的肿瘤抑制作用。为了测试PTEN在Pre-B急性淋巴细胞白血病(ALL)中的肿瘤抑制作用，我们在Pre-B ALL小鼠模型中诱导了Pten的Cre介导的缺失。与Pten在其他癌症中作为肿瘤抑制因子的作用不同，Pten的一个或两个等位基因的缺失会导致Pre-B ALL细胞迅速死亡，并足以清除移植受体小鼠的白血病。小分子抑制人Pre-B-ALL细胞的PTEN可导致AKT过度激活、P53检查点激活和细胞死亡。Pre-B ALL细胞中PTEN功能的丧失在功能上等同于自身反应性Pre-BCR信号的急性激活，后者参与了去除自身反应性B细胞的缺失检查点。我们认为，靶向抑制PTEN和AKT的过度激活触发了消除自身反应性B细胞的检查点，并代表了克服人类ALL耐药的新策略。
PTEN is a negative regulator of PI3K-AKT signaling and a potent tumor suppressor in many types of cancer. To test a tumor suppressive role of PTEN in pre-B acute lymphoblastic leukemia (ALL), we induced Cre-mediated deletion of Pten in mouse models of pre-B ALL. In contrast to its role as a tumor suppressor in other cancers, loss of one or both alleles of Pten caused rapid cell death of pre-B ALL cells and was sufficient to clear transplant recipient mice of leukemia. Small molecule inhibition of PTEN in human pre-B ALL cells resulted in AKT hyperactivation, p53 checkpoint activation and cell death. Loss of PTEN function in pre-B ALL cells was functionally equivalent to acute activation of autoreactive pre-BCR signaling, which engaged a deletional checkpoint for removal of autoreactive B cells. We propose that targeted inhibition of PTEN and hyperactivation of AKT triggers a checkpoint for elimination of autoreactive B cells and represents a new strategy to overcome drug-resistance in human ALL.
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DOI：
10.1084/jem.20091962
发表时间：
2010-10-25
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Miletic AV;Anzelon-Mills AN;Mills DM;Omori SA;Pedersen IM;Shin DM;Ravetch JV;Bolland S;Morse HC 3rd;Rickert RC
通讯作者：
Rickert RC
DOI：
10.1038/nrc1299
发表时间：
2004-03
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
影响因子：
1.5
作者：
Lesche, R;Groszer, M;Wu, H
通讯作者：
Wu, H
影响因子：
20.3
作者：
Aiba, Yuichi;Kameyama, Megumi;Kurosaki, Tomohiro
通讯作者：
Kurosaki, Tomohiro
影响因子：
20.3
作者：
Li, Yitang;Prasad, Amit;Luo, Hongbo R.
通讯作者：
Luo, Hongbo R.