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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >AML1-ETO and C-KIT mutation/overexpression in t(8;21) leukemia: implication in stepwise leukemogenesis and response to Gleevec.
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AML1-ETO and C-KIT mutation/overexpression in t(8;21) leukemia: implication in stepwise leukemogenesis and response to Gleevec.

机译：AML1-ETO和C-KIT突变/在t（8; 21）白血病中的过度表达：逐步白血病的发生和对格列卫的反应。

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摘要

To explore the genetic abnormalities that cooperate with AML1-ETO (AE) fusion gene to cause acute myeloid leukemia (AML) with t(8;21), we screened a number of candidate genes and identified 11 types of mutations in C-KIT gene (mC-KIT), including 6 previously undescribed ones among 26 of 54 (48.1%) cases with t(8;21). To address a possible chronological order between AE and mC-KIT, we showed that, among patients with AE and mC-KIT, most leukemic cells at disease presentation harbored both genetic alteration, whereas in three such cases investigated during complete remission, only AE, but not mC-KIT, could be detected by allele-specific PCR. Therefore, mC-KIT should be a subsequent event on the basis of t(8;21). Furthermore, induced expression of AE in U937-A/E cells significantly up-regulated mRNA and protein levels of C-KIT. This may lead to an alternative way of C-KIT activation and may explain the significantly higher C-KIT expression in 81.3% of patients with t(8;21) than in patients with other leukemias. These data strongly suggest that t(8;21) AML follows a stepwise model in leukemogenesis, i.e., AE represents the first, fundamental genetic hit to initiate the disease, whereas activation of the C-KIT pathway may be a second but also crucial hit for the development of a full-blown leukemia. Additionally, Gleevec suppressed the C-KIT activity and induced proliferation inhibition and apoptosis in cells bearing C-KIT N822K mutation or overexpression, but not in cells with D816 mC-KIT. Gleevec also exerted a synergic effect in apoptosis induction with cytarabine, thus providing a potential therapeutic for t(8;21) leukemia.
机译：为了探索与AML1-ETO（AE）融合基因协同作用导致t（8; 21）的急性髓性白血病（AML）的遗传异常，我们筛选了许多候选基因并鉴定了C-KIT基因的11种突变类型（mC-KIT），其中54例（48.1％）的26例中有6例先前未描述的t（8; 21）。为了解决AE和mC-KIT之间的可能的时间顺序，我们表明，在AE和mC-KIT患者中，大多数疾病表现时的白血病细胞都具有遗传变异，而在完全缓解期间研究的三个此类病例中，只有AE，但等位基因特异性PCR可以检测到mC-KIT。因此，mC-KIT应该是基于t（8; 21）的后续事件。此外，诱导的AE在U937-A / E细胞中的表达显着上调了C-KIT的mRNA和蛋白水平。这可能会导致C-KIT激活的另一种方式，并且可以解释t（8; 21）患者中81.3％的C-KIT表达明显高于其他白血病患者。这些数据有力地表明，t（8; 21）AML在白血病发生中遵循逐步模型，即AE代表引发该疾病的第一个基本的基因打击，而C-KIT途径的激活可能是第二个但也是关键的打击用于发展成熟的白血病。此外，格列卫抑制了具有C-KIT N822K突变或过度表达的细胞的C-KIT活性，并诱导了增殖抑制和凋亡，但在具有D816 mC-KIT的细胞中却没有。格列卫在阿糖胞苷诱导凋亡的过程中也发挥了协同作用，从而为t（8; 21）白血病提供了潜在的治疗方法。

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