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Disentangling the microRNA regulatory milieu in multiple myeloma: integrative genomics analysis outlines mixed miRNA-TF circuits and pathway-derived networks modulated in t(4;14) patients

机译:解开多发性骨髓瘤中的microRNA调节环境:综合基因组学分析概述了在t(4; 14)患者中调制的混合miRNA-TF电路和途径衍生网络

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摘要

The identification of overexpressed miRNAs in multiple myeloma (MM) has progressively added a further level of complexity to MM biology. miRNA and gene expression profiles of two large representative MM datasets, available from retrospective and prospective series and encompassing a total of 249 patients at diagnosis, were analyzed by means of in silico integrative genomics methods, based on MAGIA2 and Micrographite computational procedures. We first identified relevant miRNA/transcription factors/target gene regulation circuits in the disease and linked them to biological processes. Members of the miR-99b/let-7e/miR-125a cluster, or of its paralog, upregulated in t(4;14), were connected with the specific transcription factors PBX1 and CEBPA and several target genes. These results were validated in two additional independent plasma cell tumor datasets. Then, we reconstructed a non-redundant miRNA-gene regulatory network in MM, linking miRNAs, such as let-7g, miR-19a, mirR-20a, mir-21, miR-29 family, miR-34 family, miR-125b, miR-155, miR-221 to pathways associated with MM subtypes, in particular the ErbB, the Hippo, and the Acute myeloid leukemia associated pathways.
机译:多发性骨髓瘤(MM)中过表达的miRNA的鉴定已逐渐将MM生物学的复杂性进一步提高。通过计算机整合基因组学方法,基于MAGIA 2 分析了两个大的代表性MM数据集的miRNA和基因表达谱,这些数据集来自回顾性研究和前瞻性研究,涵盖了249位患者。和显微石墨计算程序。我们首先确定了疾病中相关的miRNA /转录因子/靶基因调控回路,并将其与生物学过程联系起来。在t(4; 14)中上调的miR-99b / let-7e / miR-125a簇成员或其旁系同源物与特定的转录因子PBX1和CEBPA以及几个靶基因相关。这些结果在另外两个独立的浆细胞肿瘤数据集中得到了验证。然后,我们在MM中重建了一个非冗余的miRNA基因调控网络,连接了诸如let-7g,miR-19a,mirR-20a,mir-21,miR-29家族,miR-34家族,miR-125b等miRNA。 ,miR-155,miR-221等与MM亚型相关的途径,尤其是与ErbB,Hippo和急性髓性白血病相关的途径。

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