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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Sustained suppression of Bcr-Abl-driven lymphoid leukemia by microRNA mimics
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Sustained suppression of Bcr-Abl-driven lymphoid leukemia by microRNA mimics

机译：microRNA模拟物持续抑制Bcr-Abl驱动的淋巴白血病

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摘要

Many cancers and leukemias are associated with strong dominant oncogenic mutations that activate tyrosine kinases and other classes of molecules, including transcription factors and antiapo-ptotic mechanisms. Some of these events can be targeted with small molecules or antibody-based therapeutics, but many remain intractable. In addition, cancer-related enzyme targets can often mutate, and drug-resistant variants are selected. Therapies directed at the mRNA encoding dominant oncogenes could provide a more global set of technologies for cancer treatment. To test this concept, we have used the model of transformation of hemato-poietic cells by the chimeric Bcr-Abl oncogene, a highly activated tyrosine kinase. Our results show that tandem arrays of miRNA mimics, but not single miRNA mimics, directed against the Abl portion of the mRNA and introduced by lentiviral vectors can effectively alter the leukemogenic potency when the degree of suppression of expression of Bcr-Abl is reduced > 200-fold from control levels. Only methods capable of such dramatic sustained reduction in the level of expression of highly activated kinase oncogenes are likely to be effective in controlling malignant cell populations.
机译：许多癌症和白血病都与强的显性致癌突变有关，这些突变激活酪氨酸激酶和其他种类的分子，包括转录因子和抗凋亡机制。这些事件中的一些可以用小分子或基于抗体的疗法来靶向，但是许多仍然难以解决。另外，与癌症相关的酶靶标经常会发生突变，并选择了耐药变异体。针对编码显性致癌基因的mRNA的疗法可能会提供一套更全面的癌症治疗技术。为了测试这个概念，我们使用了由嵌合Bcr-Abl癌基因（一种高度活化的酪氨酸激酶）转化造血细胞的模型。我们的结果表明，当抑制Bcr-Abl表达的程度降低> 200时，针对mRNA的Abl部分并由慢病毒载体引入的miRNA模拟物的串联阵列，而不是单个miRNA模拟物，可以有效改变白血病发生潜能。 -从控制水平折叠。只有能够显着持续降低高度活化的激酶癌基因表达水平的方法才可能有效控制恶性细胞群。

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