A set of miRNAs that involve in the pathways of drug resistance and leukemic stem-cell differentiation is associated with the risk of relapse and glucocorticoid response in childhood ALL.
A set of miRNAs that involve in the pathways of drug resistance and leukemic stem-cell differentiation is associated with the risk of relapse and glucocorticoid response in childhood ALL.
复制标题
一组参与耐药性和白血病干细胞分化途径的 miRNA 与儿童 ALL 的复发风险和糖皮质激素反应相关
DOI：
10.1093/hmg/ddr428
复制
发表时间：
2011-12-15
影响因子：
3.5
通讯作者：
Chen YQ
中科院分区：
文献类型：
--
作者：
Han BW;Feng DD;Li ZG;Luo XQ;Zhang H;Li XJ;Zhang XJ;Zheng LL;Zeng CW;Lin KY;Zhang P;Xu L;Chen YQ
复发是成功治疗儿童急性淋巴细胞白血病（ALL）的主要挑战。尽管进行了大量的研究，但ALL复发的机制仍未完全了解。需要了解治疗结果、治疗反应和复发生物学的分子机制。在这项研究中，我们进行了全基因组microRNA （miRNA）微阵列分析，以确定一组匹配的诊断-复发或诊断-完全缓解（CR）儿童ALL样本中的miRNA表达谱和复发相关的miRNA模式。在一组独立的样本中，通过定量实时聚合酶链反应进一步验证了一组在复发患者中或诊断时与CR相比差异表达的mirna。基于基因本体“生物学过程”分类对靶基因的预测功能进行分析，发现异常表达的mirna与肿瘤发生、经典多药耐药途径和白血病干细胞自我更新和分化途径相关。实验验证了与ALL复发相关的几个mirna靶标，包括FOXO3、BMI1和E2F1。我们进一步研究了这些失调的mirna与临床结果的关联，并证实了miR-708、miR-223和miR-27a与个体无复发生存期的显著关联。值得注意的是，miR-708还被发现与体内糖皮质激素治疗反应和疾病风险分层相关。这些mirna及其靶点可能用于优化抗白血病治疗，并为开发新的白血病对策提供新的靶点。这项基础研究也可能有助于建立其他癌症复发的机制。
Relapse is a major challenge in the successful treatment of childhood acute lymphoblastic leukemia (ALL). Despite intensive research efforts, the mechanisms of ALL relapse are still not fully understood. An understanding of the molecular mechanisms underlying treatment outcome, therapy response and the biology of relapse is required. In this study, we carried out a genome-wide microRNA (miRNA) microarray analysis to determine the miRNA expression profiles and relapse-associated miRNA patterns in a panel of matched diagnosis–relapse or diagnosis–complete remission (CR) childhood ALL samples. A set of miRNAs differentially expressed either in relapsed patients or at diagnosis compared with CR was further validated by quantitative real-time polymerase chain reaction in an independent sample set. Analysis of the predicted functions of target genes based on gene ontology ‘biological process’ categories revealed that the abnormally expressed miRNAs are associated with oncogenesis, classical multidrug resistance pathways and leukemic stem cell self-renewal and differentiation pathways. Several targets of the miRNAs associated with ALL relapse were experimentally validated, including FOXO3, BMI1 and E2F1. We further investigated the association of these dysregulated miRNAs with clinical outcome and confirmed significant associations for miR-708, miR-223 and miR-27a with individual relapse-free survival. Notably, miR-708 was also found to be associated with the in vivo glucocorticoid therapy response and with disease risk stratification. These miRNAs and their targets might be used to optimize anti-leukemic therapy, and serve as novel targets for development of new countermeasures of leukemia. This fundamental study may also contribute to establish the mechanisms of relapse in other cancers.
登录
查看更多内容
影响因子：
6.4
作者：
Chintharlapalli, Sudhakar;Papineni, Sabitha;Abdelrahim, Maen;Abudayyeh, Ala;Jutooru, Indira;Chadalapaka, Gayathri;Wu, Fei;Mertens-Talcott, Susanne;Vanderlaag, Kathy;Cho, Sung Dae;Smith, Roger, III;Safe, Stephen
通讯作者：
Safe, Stephen
影响因子：
168.9
作者：
BRISCO, MJ;CONDON, J;MORLEY, AA
通讯作者：
MORLEY, AA
影响因子：
158.5
作者：
Cavé, H;ten Bosch, JV;Vilmer, E
通讯作者：
Vilmer, E
影响因子：
20.3
作者：
Coustan-Smith, E;Sancho, J;Campana, D
通讯作者：
Campana, D
影响因子：
6.5
作者：
Beesley, AH;Cummings, AJ;Kees, UR
通讯作者：
Kees, UR