IKZF1缺失通过整合素信号促中枢神经系统白血病的作用及机制研究

中枢神经系统白血病（CNSL）是儿童急性淋巴细胞白血病（ALL）治疗的难题，探索相关分子生物学特征及潜在干预靶点具有重要意义。申请人和同行前期发现抑癌基因IKZF1缺失的ALL患者极易合并CNSL，机制尚未明确。预实验中，申请人通过细胞共培养发现IKZF1缺失ALL细胞更易与脑膜细胞粘附并耐药；转录组测序提示IKZF1缺失患者脑脊液中细胞粘附信号通路明显上调，其中整合素表达增高。整合素是肿瘤细胞与其微环境间相互作用的主要介质，因此我们推测IKZF1缺失可能通过激活整合素信号影响脑膜微环境中ALL细胞的粘附及存活而促进CNSL的发生。本项目拟采用患者原代样本、细胞共培养和模式动物，进一步明确IKZF1缺失在CNSL中的作用；探究IKZF1缺失激活整合素的分子机制；评估整合素阻断剂对CNSL的疗效。本项目将揭示IKZF1-整合素通路调控CNSL的分子新机制，为CNSL的靶向治疗提供新思路。

Central nervous system leukemia (CNSL) is a difficulty in the treatment of children's acute lymphoblastic leukemia (ALL). It is important to explore relevant molecular biological characteristics and potential targets. We and others previously found that ALL patients with IKZF1 deletion were susceptible to CNSL and the mechanism was not clear. By in vitro cell co-culture, we found that IKZF1 deletion ALL cells were more likely to adhere to meningeal cells and develop drug resistance. Transcriptome sequencing suggested that up-regulated genes in cerebrospinal fluid of IKZF1 deleted patients were highly enriched in the cell adhesion pathway, in which the expression of integrin was increased. Integrin plays an important role in the interaction between tumor cells and their microenvironment. Therefore, it is speculated that IKZF1 deletion may promote CNSL by activating integrin and affecting the adhesion and survival of ALL cells in meningeal microenvironment. In this study, through clinical samples, cell co-culture and model animals, we will further clarify the role of IKZF1 deletion in CNSL, explore the molecular mechanism of IKZF1 deletion activating integrin, evaluate the efficacy of integrin blockers in CNSL. This project will reveal the new molecular mechanism of IKZF1-integrin pathway regulating CNSL and provide new ideas for targeted therapy of CNSL.