调控网络分析揭示了正反馈环在 T 细胞急性淋巴细胞白血病中的致癌作用和治疗靶点。

Regulatory network analysis reveals the oncogenesis roles of feed-forward loops and therapeutic target in T-cell acute lymphoblastic leukemia.

机构信息

Hubei Bioinformatics and Molecular Imaging Key Laboratory, Department of Bioinformatics and Systems Biology, Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, 1037 Luoyu Road, Wuhan, 430074, China.

Department of Hematology, the Second Hospital of Shandong University, Jinan, 250033, Shandong, China.

出版信息

BMC Med Genomics. 2019 Jan 15;12(1):8. doi: 10.1186/s12920-018-0469-0.

DOI:10.1186/s12920-018-0469-0

PMID:30646895

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6332896/

Abstract

BACKGROUND

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy. Aberrant expressed genes contribute to the development and progression of T-ALL. However, the regulation underlying their aberrant expression remains elusive. Dysregulated expression of transcription factors and miRNAs played important regulatory roles in the pathogenesis of T-ALL.

METHODS

In this study, we analyzed the alteration of transcriptome profiling and regulatory networks between T-ALL sample and normal T cell samples at transcriptional and post-transcriptional levels.

RESULTS

Our results demonstrated that genes related to cell cycle and cell proliferation processes were significantly upregulated in T-ALL comparing to normal samples. Meanwhile, regulatory network analyses revealed that FOXM1, MYB, SOX4 and miR-21/19b as core regulators played vital roles in the development of T-ALL. FOXM1-miR-21-5p-CDC25A and MYB/SOX4-miR-19b-3p-RBBP8 were identified as important feed-forward loops involved in the oncogenesis of T-ALL. Drug-specific analyses showed that GSK-J4 may be an effective drug, and CDC25A/CAPN2/MCM2 could serve as potential therapeutic targets for T-ALL.

CONCLUSIONS

This study may provide novel insights for the regulatory mechanisms underlying the development of T-ALL and potential therapeutic targets.

摘要

背景

T 细胞急性淋巴细胞白血病（T-ALL）是一种侵袭性血液恶性肿瘤。异常表达的基因有助于 T-ALL 的发生和发展。然而，它们异常表达的调节机制仍不清楚。转录因子和 miRNA 的失调表达在 T-ALL 的发病机制中发挥着重要的调节作用。

方法

在这项研究中，我们分析了 T-ALL 样本与正常 T 细胞样本在转录和转录后水平上的转录组谱和调控网络的改变。

结果

我们的结果表明，与正常样本相比，T-ALL 中与细胞周期和细胞增殖过程相关的基因显著上调。同时，调控网络分析显示，FOXM1、MYB、SOX4 和 miR-21/19b 作为核心调控因子，在 T-ALL 的发生发展中发挥着重要作用。FOXM1-miR-21-5p-CDC25A 和 MYB/SOX4-miR-19b-3p-RBBP8 被确定为参与 T-ALL 发生的重要前馈环。药物特异性分析表明，GSK-J4 可能是一种有效的药物，CDC25A/CAPN2/MCM2 可以作为 T-ALL 的潜在治疗靶点。