混合系白血病是由MLL基因发生染色体易位形成多种融合蛋白而引起的一种急性白血病。转录延伸复合物（SEC）在混合系白血病的发生发展过程中发挥重要功能。目前针对混合系白血病虽已有多种抑制剂，但均未依据致病机制的关键步骤设计而治疗效果不佳。因此，申请人预实验采用课题组前期研发的靶向SEC的抑制剂KL-1/2作用于混合系白血病细胞并发现：KL-1/2显著抑制了细胞增殖，促进了细胞凋亡，抑制了细胞中参与造血功能等关键生理过程的主导靶标基因（LMRs）新生RNA合成和转录延伸。本研究拟首先在细胞水平上阐明KL-1/2对细胞增殖、凋亡、分化影响的现象，然后采用ChIP-seq，TT-seq、4sU-FP-seq等前沿技术阐释KL-1/2调节LMRs转录的分子机制，最后在动物模型中验证KL-1/2的干预效果。因此，本研究不仅证明通过靶向SEC治疗混合系白血病的可能性，并为其他侵袭性疾病提供实用的治疗思路。

Mixed Lineage Leukemia is an aggressive leukemia and is driven by the chromosomal translocations of MLL gene with various partner genes. Super Elongation Complex (SEC) plays a crucial role in the leukemogenesis and maintenance of Mixed Lineage Leukemia. Although a few inhibitors have been tried in the Mixed Lineage Leukemia, they are not designed to target the key steps of the MLL pathogenesis and the therapeutic effect is generally poor. Here, we tried the SEC inhibitors KL-1/2 that were developed by our group in Mixed Lineage Leukemia and found that the SEC disruption with the KL-1/2 impeded the proliferation and induced apoptosis of Mixed Lineage Leukemia cells. Mechanistically, we found that KL-1/2 inhibited the nascent RNA synthesis and blocked the transcriptional elongation of Leukemia Master Regulators (LMRs), which are involved in hemopoiesis and Mixed Lineage Leukemia pathogenesis. In this study, we are trying to target SEC in Mixed Lineage Leukemia with small-molecular inhibitors KL-1/2. First, we will check the effects of KL-1/2 on the cell proliferation and apoptosis of Mixed Lineage Leukemia cells, then we will investigate the underlying molecular mechanism by studying the transcriptional regulation of LMRs after SEC disruption. Furthermore, we will test the therapeutic effects of KL-1/2 in Mixed Lineage Leukemia animal models. The project will not only prove the possibility of targeting SEC in Mixed Lineage Leukemia, but also provide practical approaches for the treatment of these aggressive diseases.