Zhu Yong-Mei, Zhao Wei-Li, Fu Jian-Fei, Shi Jing-Yi, Pan Qin, Hu Jiong, Gao Xiao-Dong, Chen Bing, Li Jun-Min, Xiong Shu-Min, Gu Long-Jun, Tang Jing-Yi, Liang Hui, Jiang Hui, Xue Yong-Quan, Shen Zhi-Xiang, Chen Zhu, Chen Sai-Juan
State Key Laboratory for Medical Genomics, Shanghai Institute of Hematology, Shanghai Rui Jin Hospital, Medical School of Shanghai Jiao Tong University, Shanghai, China.
Clin Cancer Res. 2006 May 15;12(10):3043-9. doi: 10.1158/1078-0432.CCR-05-2832.
NOTCH signaling pathway is essential in T-cell development and NOTCH1 mutations are frequently present in T-cell acute lymphoblastic leukemia (T-ALL). To gain insight into its clinical significance, NOTCH1 mutation was investigated in 77 patients with T-ALL.
Detection of NOTCH1 mutation was done using reverse transcription-PCR amplification and direct sequencing, and thereby compared according to the clinical/biological data of the patients.
Thirty-two mutations were identified in 29 patients (with dual mutations in 3 cases), involving not only the heterodimerization and proline/glutamic acid/serine/threonine domains as previously reported but also the transcription activation and ankyrin repeat domains revealed for the first time. These mutations were significantly associated with elevated WBC count at diagnosis and independently linked to short survival time. Interestingly, the statistically significant difference of survival according to NOTCH1 mutations was only observed in adult patients (>18 years) but not in pediatric patients (< or = 18 years), possibly due to the relatively good overall response of childhood T-ALL to the current chemotherapy. NOTCH1 mutations could coexist with HOX11, HOX11L2, or SIL-TAL1 expression. The negative effect of NOTCH1 mutation on prognosis was potentiated by HOX11L2 but was attenuated by HOX11.
NOTCH1 mutation is an important prognostic marker in T-ALL and its predictive value could be even further increased if coevaluated with other T-cell-related regulatory genes. NOTCH pathway thus acts combinatorially with oncogenic transcriptional factors on T-ALL pathogenesis.
Notch信号通路在T细胞发育过程中至关重要，Notch1突变在T细胞急性淋巴细胞白血病（T-ALL）中频繁出现。为深入了解其临床意义，对77例T-ALL患者进行了Notch1突变研究。
采用逆转录-PCR扩增和直接测序检测Notch1突变，并根据患者的临床/生物学数据进行比较。
在29例患者中鉴定出32个突变（3例为双重突变），不仅涉及先前报道的异二聚化结构域和脯氨酸/谷氨酸/丝氨酸/苏氨酸结构域，还首次发现了转录激活结构域和锚蛋白重复结构域。这些突变与诊断时白细胞计数升高显著相关，且独立与生存时间缩短有关。有趣的是，根据Notch1突变的生存差异仅在成年患者（>18岁）中观察到，而在儿童患者（≤18岁）中未观察到，这可能是由于儿童T-ALL对当前化疗的总体反应相对较好。Notch1突变可与HOX11、HOX11L2或SIL-TAL1表达共存。HOX11L2增强了Notch1突变对预后的负面影响，而HOX11则减弱了这种影响。
Notch1突变是T-ALL的重要预后标志物，如果与其他T细胞相关调节基因共同评估，其预测价值可能会进一步提高。因此，Notch通路在T-ALL发病机制中与致癌转录因子协同发挥作用。
