NR3C1基因突变在成人急性淋巴细胞白血病耐药与复发中的作用与机制研究

项目名称： NR3C1基因突变在成人急性淋巴细胞白血病耐药与复发中的作用与机制研究

项目编号： No.81470309

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 肖浩文

作者单位： 浙江大学

项目金额： 75万元

中文摘要： 难治、复发是影响急性淋巴细胞白血病（Acute Lymphoblastic Leukemia, ALL）患者获得长期生存的首要障碍，发现新的复发相关基因突变不仅有助于深入理解ALL复发的发生机制，还有助于探索有效的干预治疗靶点。本课题组在前期研究中，首次利用全基因组外显子测序技术筛选出成人ALL发生异基因造血干细胞移植后复发时，复发白血病细胞特异性获得糖皮质激素受体编码基因—NR3C1基因突变，且突变位点位于蛋白的糖皮质激素受体功能区域。本项目拟在前期研究基础上进一步围绕发现的NR3C1基因第2号外显子两个突变位点（exon2:c.431_431 delinsAG；exon2: c.640C>T），首次通过临床研究、体外细胞实验和基因定点突变动物模型研究明确NR3C1基因突变对糖皮质激素受体蛋白功能、糖皮质激素促白血病细胞凋亡信号通路的影响，及诱导ALL耐药和复发的分子机制。

中文关键词： 急性淋巴细胞白血病；复发；治疗耐药；NR3C1；基因突变

英文摘要： Drug-resistance and disease relapse are the leading causes of death in adult patients with acute lymphoblastic leukemia (ALL). Several adverse genetic alterations-including rearrangement of the myeloid-lymphoid or mixed-lineage leukemia genes and Philadelphia (Ph) chromosome - are responsible for treatment failure and relapse in ALL. However, many Ph chromosome-negative (Ph?) ALL patients with normal karyotype and who lack documented risk factors also experience relapse. The pathologic determinants and prognostic markers in these cases remain poorly understood. In our previous study, we performed longitudinal whole-exome sequencing analysis in matched samples from adult patients with Philadelphia chromosome-negative (Ph?) B-cell acute lymphoblastic leukemia (Ph? B-ALL) from diagnosis to relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We found that the NR3C1 gene, encoding a transcription factor/glucocorticoid receptor, was selectively mutated in relapsed samples from two cases and is therefore a putative relapse-specific mutation in adult ALL. Furthermore, mutations within the NR3C1 genes occurred exclusively in sites that are highly conserved across species and were distributed in glucocorticoid receptor functional domains, which would be predicted to result in the loss of protein function. Based on our previous study findings, in the present study, we attempt to elucidate the role and mechanisms of NR3C1 gene mutations in drug-resistance and relapse of ALL by ex vivo cell studies, transplantation animal model studies and gene mutation knock-in mouse model studies. Our study may provide valuable information to research of the mechanisms of leukemia relapse and drug-resistance and improve the survival of adult ALL patients.

英文关键词： Acute Lymphoblastic Leukemia;Relapse;Drug-resistance;NR3C1;Gene Mutation