A novel mutation in the miR-128b gene reduces miRNA processing and leads to glucocorticoid resistance of MLL-AF4 acute lymphocytic leukemia cells.
A novel mutation in the miR-128b gene reduces miRNA processing and leads to glucocorticoid resistance of MLL-AF4 acute lymphocytic leukemia cells.
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DOI：
10.4161/cc.9.6.11011
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发表时间：
2010-03-15
期刊：
影响因子：
--
通讯作者：
Lodish HF
中科院分区：
文献类型：
--
作者：
Kotani A;Ha D;Schotte D;den Boer ML;Armstrong SA;Lodish HF
MLL-AF4急性淋巴细胞白血病预后较差，尽管基于众所周知的概念和方法进行了深入的研究，但这些白血病的发病机制尚不清楚。MicroRNAs(MiRNAs)是一类新的非编码小RNA，它在转录后调节靶mRNA转录本的表达。我们最近报道，在MLL-AF4 ALL中下调的两个miRNAs miR-128B和miR-221的异位表达，通过下调染色体易位产生的MLL-AF4和AF4-MLL嵌合蛋白MLL-AF4和AF4-MLL来恢复糖皮质激素抵抗。在这里，我们报告了在来自MLL-AF4 ALL患者的RS4；11细胞中发现miR-128B的新突变。一种新的突变显著减少了miR-128B的处理。最后，这种碱基改变发生在最初的MLL-AF4 ALL样本中，作为获得性突变。这些结果表明，MLL-AF4中miR-128B的新突变都改变了miR-128B的加工过程，由此导致的成熟miR-128B的下调通过未能下调融合癌基因而导致糖皮质激素抵抗。
MLL-AF4 Acute Lymphocytic Leukemia has a poor prognosis, and the mechanisms by which these leukemias develop are not understood despite intensive research based on well-known concepts and methods. MicroRNAs (miRNAs) are a new class of small noncoding RNAs that post-transcriptionally regulate expression of target mRNA transcripts. We recently reported that ectopic expression of miR-128b together with miR-221, two of the miRNAs downregulated in MLL-AF4 ALL, restores glucocorticoid resistance through downregulation of the MLL-AF4 chimeric fusion proteins MLL-AF4 and AF4-MLL that are generated by chromosomal translocation t(4;11). Here we report the identification of new mutations in miR-128b in RS4;11 cells, derived from MLL-AF4 ALL patient. One novel mutation significantly reduces the processing of miR-128b. Finally, this base change occurs in a primary MLL-AF4 ALL sample as an acquired mutation. These results demonstrate that the novel mutation in miR-128b in MLL-AF4 ALL alters the processing of miR-128b and that the resultant downregulation of mature miR-128b contributes to gluco-corticoid resistance through the failure to downregulate the fusion oncogenes.
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影响因子：
64.8
作者：
Lu, J;Getz, G;Golub, TR
通讯作者：
Golub, TR
影响因子：
168.9
作者：
Pieters, Rob;Schrappe, Martin;Valsecchi, Maria Grazia
通讯作者：
Valsecchi, Maria Grazia
DOI：
10.1073/pnas.0602266103
发表时间：
2006-05-02
影响因子：
11.1
作者：
Costinean, S;Zanesi, N;Croce, CM
通讯作者：
Croce, CM
DOI：
10.1073/pnas.0506464102
发表时间：
2005-09-27
影响因子：
11.1
作者：
Xia, ZB;Popovic, R;Zeleznik-Le, NJ
通讯作者：
Zeleznik-Le, NJ
影响因子：
20.3
作者：
Kotani, Ai;Ha, Daon;Lodish, Harvey F.
通讯作者：
Lodish, Harvey F.