IK6通过LncRNA CCDC26-RNase P复合体参与调控急性淋巴细胞白血病生物学行为的机制研究

IK6是急性淋巴细胞白血病（ALL）常见的一种IKZF1缺失突变亚型，在ALL病理过程和预后发挥重要作用，但其作用机制尚待阐明。本课题组发现，IK6过表达ALL细胞株G0/G1期比例增多、迁移黏附能力增强、化疗敏感性下降；同时IK6与野生型IKZF1相互作用上调LncRNA CCDC26，在ALL细胞中过表达LncRNA CCDC26显现出与IK6相似的生物学效应；功能研究显示LncRNA CCDC26可作为先导链与RNase P亚基Rpp25、Rpp38结合。因此我们提出IK6的新作用机制：IK6以显性负性体方式拮抗IKZF1介导的LncRNA CCDC26转录抑制，进而上调LncRNA CCDC26，后者以先导链形式组装RNase P复合体参与调控ALL生物学行为。本课题将从分子、细胞、动物水平开展研究验证这一假说，并评价靶向LncRNA CCDC26对ALL细胞生物学行为的逆转作用。

IK6, a well-known isoform of IKZF1 deletion mutants in acute lymphoblastic leukemia (ALL), plays a key role in pathogenesis and prognosis of ALL. However, its role and mechanism remain undetermined. We have found that IK6 overexpression in ALL cell line leads to increase of G0/G1 cell cycle arrest, enhancement of migration and adhesion, as well as resistance to chemotherapy. Interestingly, IK6 interacted with wild type IKZF1 as forming heterodimerization and upregulated LncRNA CCDC26 expression. Moreover, ALL cells with expressing an exogenous LncRNA CCDC26 showed similar biological behaviors as those with IK6 alteration. In addition, functional analysis demonstrated LncRNA CCDC26 bound to Rpp25 and Rpp38, two subunits of RNase P. Therefore, we supposed that IK6 upregulates LncRNA CCDC26 through interfering with IKZF1-mediated transcriptional repression and LncRNA CCDC26 acts as an RNA introducer strand to guide assembling of RNase P, which ultimately orchestrates the biological behaviors of ALL cells. In this study, we will further verify our hypothesis by carrying out relevant experiments from the molecular, cellular and animal model. At the same time, we will evaluate the therapeutic effect of targeting LncRNA CCDC26 in combination with traditional chemotherapy on eradicating ALL cells.