儿童和成人急性T淋巴细胞白血病中miRNA和转录因子共调控网络的差异性研究

T-cell acute lymphoblastic leukemia (T-ALL) is a serious disease damaging human being's health. Adult T-ALL patients have a worse prognosis, with a much lower disease-free survival rates than childhood T-ALL patients and the mechanism of the difference is unknown. Transcription factor (TF) and miRNA are both key regulators of gene expression. We have developed an approach to study their co-regulatory network in complex diseases. In this study, based on our previous work, we proposed to study the different mechanisms of childhood and adult T-ALL based on the miRNA and TF co-regulatory network. Firstly, we will characterize the differential genes and miRNAs between childhood and adult T-ALL patients by high-throughput sequencing. Based on these genes and miRNAs, we will construct the miRNA-TF feed forward loop and co-regulatory network and further analyze the effects of miRNA-related SNPs on this network. Then, we will identify the key regulators and modules in the network and analyze their functions in the childhood and adult T-ALL. Finally, we will perform experiments to confirm the regulatory relationship of the key modules, study the effects of miRNAs on the T-ALL cell proliferation, migration, and the survive of T-ALL mice. This study will provide new insights and regulatory mechanisms in the difference of childhood and adult T-ALL cure. Also provides research bases to identify potential targets, prognosis markers, and interventions. It has potential application value and significance on disease study.

急性T淋巴细胞白血病（T-ALL）严重危害人类健康，其中成人患者的疗效明显差于儿童，且分子机制不明。转录因子（TF）和miRNA 均为重要的基因表达调控因子。基于我们前期成功建立的miRNA和TF在复杂疾病中的共调控网络研究方法，本项目拟研究儿童和成人T-ALL之间的差异调控机制。首先采用高通量测序方法鉴定儿童和成人T-ALL中的差异基因和miRNA，构建差异miRNA和TF共调控前馈环模块及网络，然后分析miRNA相关SNP对该网络的影响。综合分析筛选调控网络中的关键miRNA和模块，探讨其在儿童和成人T-ALL中的差异性作用。最后实验验证调控模块，并在体外和体内验证miRNA对T-ALL细胞增殖、迁移和凋亡等特征的影响及对T-ALL模型小鼠的影响。本项目为揭示儿童和成人T-ALL的疗效差异性提供新的调控机制，为发现潜在的重要靶标和干预手段提供基础，具有重要的应用价值和学术意义。

白血病是恶性程度很高的血液肿瘤，其在儿童及青少年人中位居恶性肿瘤死亡率的首位。急性淋巴细胞白血病（Acute lymphoblastic leukemia，ALL）是白血病的常见类型，包括急性T淋巴细胞白血病和急性B淋巴细胞白血病，也是儿童白血病的主要类型。儿童和成人ALL疗效存在明显差异，成人ALL的5年无病生存率只有儿童ALL的一半，导致儿童和成人T-ALL最终疗效差异性的分子机制和原因目前还不清楚。因此，本项目旨在研究和解析其致病机理和差异性调控机制，寻找导致成人T-ALL预后差的关键机制和治疗靶标。在研究中，我们升级了动物转录因子数据库AnimalTFDB，整合研究了人类转录因子ChIP-Seq数据，完善了转录因子与miRNA共调控网络研究方法和数据。测序了5对儿童与成人ALL的初治样本数据（包括RNA-Seq和miRNA-Seq），分析鉴定了儿童和成人淋巴细胞白血病中的差异基因326个和差异miRNA18个，发现这些差异基因多数都在成人中下调。构建了转录因子和miRNA对差异基因的共调控前馈环模块和网络，筛选了一些核心模块和基因，用于后续实验验证。同时分析B和T淋巴细胞发育过程中的转录因子和miRNA共调控模块和网络，发现不同阶段共有的关键调控因子。本项目研究通过高通量测序和调控网络方法筛选了一些儿童与成人淋巴细胞白血病的重要差异基因，获得了潜在差异靶标进行验证。