Up-regulation of a HOXA-PBX3 homeobox-gene signature following down-regulation of miR-181 is associated with adverse prognosis in patients with cytogenetically abnormal AML
Up-regulation of a HOXA-PBX3 homeobox-gene signature following down-regulation of miR-181 is associated with adverse prognosis in patients with cytogenetically abnormal AML
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miR-181 下调后 HOXA-PBX3 同源盒基因特征的上调与细胞遗传学异常 AML 患者的不良预后相关
DOI：
10.1182/blood-2011-10-386235
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发表时间：
2012-03-08
期刊：
影响因子：
20.3
通讯作者：
Chen, Jianjun
中科院分区：
文献类型：
--
作者：
Li, Zejuan;Huang, Hao;Chen, Jianjun
miR - 181家族成员表达水平升高已被证明与细胞遗传学正常的急性髓系白血病患者的良好预后相关。在此我们表明，在细胞遗传学异常的急性髓系白血病（CA - AML）患者中，miR - 181a和miR - 181b表达升高也与良好的总生存期显著相关（P <.05；Cox回归）。我们进一步表明，由4个潜在的miR - 181靶基因（包括HOXA7、HOXA9、HOXA11和PBX3）组成的基因特征的上调，与miR - 181家族成员的下调相关，在对183例CA - AML患者的多变量分析中是不良总生存期的独立预测因子。这个4个同源盒基因特征的独立预后影响在271例CA - AML患者的验证集中得到了证实。此外，我们的体外和体内研究表明，miR - 181b的异位表达显著促进白血病细胞凋亡，抑制其活性/增殖，并延缓白血病的发生；这种效应可通过强制表达PBX3而逆转。因此，由miR - 181家族成员下调导致的4个同源盒基因的上调可能是不良CA - AML患者预后不良的原因。恢复miR - 181b的表达和/或靶向HOXA/PBX3通路可能为大幅提高生存率提供新的策略。（《血液》2012年；119(10):2314 - 2324）
Increased expression levels of miR-181 family members have been shown to be associated with favorable outcome in patients with cytogenetically normal acute myeloid leukemia. Here we show that increased expression of miR-181a and miR-181b is also significantly (P < .05; Cox regression) associated with favorable overall survival in cytogenetically abnormal AML (CA-AML) patients. We further show that up-regulation of a gene signature composed of 4 potential miR-181 targets (including HOXA7, HOXA9, HOXA11, and PBX3), associated with down-regulation of miR-181 family members, is an independent predictor of adverse overall survival on multivariable testing in analysis of 183 CA-AML patients. The independent prognostic impact of this 4-homeobox-gene signature was confirmed in a validation set of 271 CA-AML patients. Furthermore, our in vitro and in vivo studies indicated that ectopic expression of miR-181b significantly promoted apoptosis and inhibited viability/proliferation of leukemic cells and delayed leukemogenesis; such effects could be reversed by forced expression of PBX3. Thus, the up-regulation of the 4 homeobox genes resulting from the down-regulation of miR-181 family members probably contribute to the poor prognosis of patients with nonfavorable CA-AML. Restoring expression of miR-181b and/or targeting the HOXA/PBX3 pathways may provide new strategies to improve survival substantially. (Blood. 2012;119(10):2314-2324)