Integrative nucleophosmin mutation-associated microRNA and gene expression pattern analysis identifies novel microRNA - target gene interactions in acute myeloid leukemia
Integrative nucleophosmin mutation-associated microRNA and gene expression pattern analysis identifies novel microRNA - target gene interactions in acute myeloid leukemia
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DOI：
10.3324/haematol.2011.046888
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发表时间：
2011-12-01
期刊：
影响因子：
--
通讯作者：
Bullinger, Lars
中科院分区：
文献类型：
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作者：
Russ, Annika C.;Sander, Sandrine;Bullinger, Lars
背景MicroRNA是基因表达的调节因子，主要通过降低其多个靶点的mRNA水平发挥作用。已显示急性髓性白血病的microRNA表达失调，这种疾病的特征还在于与不同基因组畸变相关的基因表达改变，例如核磷蛋白（NPM 1）突变。为了进一步阐明microRNA和基因表达失调在伴有NPM 1突变的细胞遗传学正常的急性髓性白血病中的作用，我们对microRNA和mRNA表达数据集进行了整合分析。（n = 43;中位年龄46岁，范围23-60岁），已知NPM 1突变状态（n = 23突变，n = 20野生型），并对数据进行综合分析。通过定量逆转录聚合酶链反应、蛋白质印迹和荧光素酶报告基因测定验证了推定的microRNA-mRNA相互作用。对于选定的microRNA，microRNA过表达的细胞阿糖胞苷治疗的敏感性进行了测试，通过流式细胞仪的活力和细胞增殖assays.ResultsOur的综合分析microRNA和基因表达谱的并行方法导致在一个完善的列表中推定的靶基因受NPM 1突变相关的microRNA失调。在177种推定的microRNA -靶mRNA相互作用中，我们鉴定并验证了77种已知或潜在参与白血病发生的新候选物，如IRF 2-miR-20 a、KIT-miR-20 a和MN 1-miR-15 a。此外，我们的数据表明，肿瘤抑制microRNA，如miR-29 a和miR-30 c的表达失调，可能有助于阿糖胞苷的敏感性，这是观察到NPM 1突变的急性髓细胞白血病。并导致鉴定与急性髓性白血病治疗潜在相关的新型microRNA -靶基因相互作用。
BackgroundMicroRNAs are regulators of gene expression, which act mainly by decreasing mRNA levels of their multiple targets. Deregulated microRNA expression has been shown for acute myeloid leukemia, a disease also characterized by altered gene expression associated with distinct genomic aberrations such as nucleophosmin (NPM1) mutations. To shed further light on the role of deregulated microRNA and gene expression in cytogenetically normal acute myeloid leukemia with NPM1 mutation we performed an integrative analysis of microRNA and mRNA expression data sets.Design and MethodsBoth microRNA and gene expression profiles were investigated in samples from a cohort of adult cytogenetically normal acute myeloid leukemia patients (n = 43; median age 46 years, range 23-60 years) with known NPM1 mutation status (n = 23 mutated, n = 20 wild-type) and the data were integratively analyzed. Putative microRNA-mRNA interactions were validated by quantitative reverse transcriptase polymerase chain reaction, western blotting and luciferase reporter assays. For selected microRNAs, sensitivity of microRNA-overexpressing cells to cytarabine treatment was tested by FACS viability and cell proliferation assays.ResultsOur integrative approach of analyzing both microRNA- and gene expression profiles in parallel resulted in a refined list of putative target genes affected by NPM1 mutation-associated microRNA deregulation. Of 177 putative microRNA - target mRNA interactions we identified and validated 77 novel candidates with known or potential involvement in leukemogenesis, such as IRF2-miR-20a, KIT-miR-20a and MN1-miR-15a. Furthermore, our data showed that deregulated expression of tumor suppressor microRNAs, such as miR-29a and miR-30c, might contribute to sensitivity to cytarabine, which is observed in NPM1 mutated acute myeloid leukemia.ConclusionsOverall, our observations highlight that integrative data analysis approaches can improve insights into leukemia biology, and lead to the identification of novel microRNA - target gene interactions of potential relevance for acute myeloid leukemia treatment.