The impact of NOTCH1, FBW7 and PTEN mutations on prognosis and downstream signaling in pediatric T-cell acute lymphoblastic leukemia: a report from the Children's Oncology Group.
The impact of NOTCH1, FBW7 and PTEN mutations on prognosis and downstream signaling in pediatric T-cell acute lymphoblastic leukemia: a report from the Children's Oncology Group.
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NOTCH1、FBW7 和 PTEN 突变对儿童 T 细胞急性淋巴细胞白血病预后和下游信号传导的影响：儿童肿瘤学组的报告。
DOI：
10.1038/leu.2009.64
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发表时间：
2009-08
期刊：
影响因子：
11.4
通讯作者：
Matherly, L. H.
中科院分区：
文献类型：
--
作者：
Gedman, A. Larson;Chen, Q.;Desmoulin, S. Kugel;Ge, Y.;LaFiura, K.;Haska, C. L.;Cherian, C.;Devidas, M.;Linda, S. B.;Taub, J. W.;Matherly, L. H.
我们在一个明确的47例儿童T细胞急性淋巴细胞白血病（T-ALL）患者队列中探讨了NOTCH 1、FBW 7和PTEN基因突变对预后和下游信号传导的影响。在T-ALL淋巴母细胞中，我们鉴定了NOTCH 1（n=16）、FBW 7（n=5）和PTEN（n=26）的高频率突变。NOTCH 1突变导致HES 1报告基因构建体的反式激活比野生型NOTCH 1增加1.3-3.3倍;突变体FBW 7导致报告基因活性进一步增强。NOTCH 1和FBW 7突变伴随着NOTCH 1靶基因（HES 1、DELTEX 1、cMYC）的中位转录物增加。然而，这些突变均与治疗结果无关。升高的HES 1、DELTEX 1和cMYC转录物与几种化疗相关基因的转录物水平显著升高相关，包括MDR 1、ABCC 5、还原型叶酸载体、天冬酰胺合成酶、硫嘌呤甲基转移酶、Bcl-2和二氢叶酸还原酶。PTEN转录本与HES 1和cMYC转录本水平呈正相关。我们的研究结果表明，应考虑多种因素，试图确定儿童T-ALL的分子为基础的预后因素，并根据NOTCH 1信号状态，修改的类型或剂量的标准化疗药物的T-ALL，或能够靶向NOTCH 1，AKT和/或mTOR与标准化疗药物的组合可能是必要的。
We explored the impact of mutations in the NOTCH1, FBW7 and PTEN genes on prognosis and downstream signaling in a well-defined cohort of 47 pediatric T-cell acute lymphoblastic leukemia (T-ALL) patients. In T-ALL lymphoblasts, we identified high frequency mutations in NOTCH1 (n=16), FBW7 (n=5) and PTEN (n=26). NOTCH1 mutations resulted in 1.3-3.3-fold increased transactivation of a HES1 reporter construct over wild-type NOTCH1; mutant FBW7 resulted in further augmentation of reporter gene activity. NOTCH1 and FBW7 mutations were accompanied by increased median transcripts for NOTCH1 target genes (HES1, DELTEX1, cMYC). However, none of these mutations were associated with treatment outcome. Elevated HES1, DELTEX1 and cMYC transcripts were associated with significant increases in transcript levels of several chemotherapy relevant genes, including MDR1, ABCC5, reduced folate carrier, asparagine synthetase, thiopurine methyltranserase, Bcl-2 and dihydrofolate reductase. PTEN transcripts positively correlated with HES1 and cMYC transcript levels. Our results suggest that multiple factors should be considered with attempting to identify molecular-based prognostic factors for pediatric T-ALL, and depending on the NOTCH1 signaling status, modifications in the types or dosing of standard chemotherapy drugs for T-ALL, or combinations of agents capable of targeting NOTCH1, AKT and/or mTOR with standard chemotherapy agents may be warranted.
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影响因子：
32.4
作者：
Deftos, ML;Huang, E;Bevan, MJ
通讯作者：
Bevan, MJ
DOI：
10.1084/jem.20070876
发表时间：
2007-08-06
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
O'Neil J;Grim J;Strack P;Rao S;Tibbitts D;Winter C;Hardwick J;Welcker M;Meijerink JP;Pieters R;Draetta G;Sears R;Clurman BE;Look AT
通讯作者：
Look AT
影响因子：
64.5
作者：
ELLISEN, LW;BIRD, J;SKLAR, J
通讯作者：
SKLAR, J
影响因子：
50.3
作者：
Ferrando, AA;Neuberg, DS;Look, AT
通讯作者：
Look, AT
影响因子：
11.2
作者：
Malyukova, Alena;Dohda, Takeaki;Sangfelt, Olle
通讯作者：
Sangfelt, Olle