Targeting the Notch1 and mTOR pathways in a mouse T-ALL model
Targeting the Notch1 and mTOR pathways in a mouse T-ALL model
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DOI：
10.1182/blood-2008-02-136762
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发表时间：
2009-06-11
期刊：
影响因子：
20.3
通讯作者：
Kelliher, Michelle A.
中科院分区：
文献类型：
--
作者：
Cullion, Kathleen;Draheim, Kyle M.;Kelliher, Michelle A.
在T细胞急性淋巴细胞白血病(T-ALL)患者和小鼠T-ALL模型中经常检测到NOTCH1突变。体外用γ-分泌酶抑制剂(GSI)处理小鼠或人T-ALL细胞系可导致生长停滞和/或细胞凋亡。这些研究表明GSI是治疗T-ALL的潜在药物。为了确定GSI在体内是否具有抗白血病活性，我们用赋形剂或默克公司开发的GSI(MRK-003)对接近终末期的Tal1/Ink4a/Arf(+/-)白血病小鼠进行了治疗。我们发现，与赋形剂治疗的小鼠相比，GSI治疗显著延长了白血病小鼠的存活时间。在GSI处理的小鼠中，NOTCH1靶基因的表达受到抑制，凋亡细胞数量增加，表明体内抑制Notch1诱导了细胞凋亡。T-ALL细胞株也表现出PI3K/mTOR通路的激活，表明雷帕霉素可能也有治疗作用。当GSI与雷帕霉素联合应用时，mTOR激酶活性被消融，并诱导细胞凋亡。此外，GSI和雷帕霉素治疗抑制了人T-ALL的生长，并延长了小鼠异种移植模型的存活时间。这项工作支持在T-ALL中靶向NOTCH1的想法，并表明抑制mTOR和NOTCH1通路可能具有额外的疗效。(血。2009；113：6172-6181)
Mutations in NOTCH1 are frequently detected in patients with T-cell acute lymphoblastic leukemia (T-ALL) and in mouse T-ALL models. Treatment of mouse or human T-ALL cell lines in vitro with gamma-secretase inhibitors (GSIs) results in growth arrest and/or apoptosis. These studies suggest GSIs as potential therapeutic agents in the treatment of T-ALL. To determine whether GSIs have antileukemic activity in vivo, we treated near-end-stage Tal1/Ink4a/Arf(+/-) leukemic mice with vehicle or with a GSI developed by Merck (MRK-003). We found that GSI treatment significantly extended the survival of leukemic mice compared with vehicle-treated mice. Notch1 target gene expression was repressed and increased numbers of apoptotic cells were observed in the GSI-treated mice, demonstrating that Notch1 inhibition in vivo induces apoptosis. T-ALL cell lines also exhibit PI3K/mTOR pathway activation, indicating that rapamycin may also have therapeutic benefit. When GSIs are administered in combination with rapamycin, mTOR kinase activity is ablated and apoptosis induced. Moreover, GSI and rapamycin treatment inhibits human T-ALL growth and extends survival in a mouse xenograft model. This work supports the idea of targeting NOTCH1 in T-ALL and suggests that inhibition of the mTOR and NOTCH1 pathways may have added efficacy. (Blood. 2009; 113: 6172-6181)