7/7q缺失AML的PDX模型构建及新型治疗靶点探索

Chromosome abnormality is one of the hallmarks of relapse acute myeloid leukemia (AML). Chromosome abnormality of -7/del(7q) is very common in acute myeloid leukemia and associated with poor prognosis. We identified a key tumor suppressor, Mll3, in chromosome 7q in our previous work (Cancer Cell 2014), and further demonstrated that single gene loss or mutation couldn’t represent the loss of chromosome fragment in chromosome 17p in our recently work (Nature 2016). Based on these findings, we generate the patient derived xenograft (PDX) model of AML with chromosome -7/del(7q) using humanized recipient mice (NSG), and further identify the new therapeutic targets, especially the epigenetics genes that we have identified before in the mouse model. We have collected nearly 40 cases of AML patient samples, and successfully constructed more than 20 cases of AML PDX model. We found that epigenetic abnormalities play an important role in the development of AML with chromosome -7/del(7q), and identified that the epigenetic inhibitor for Brd4, JQ-1, have good intervention effect on this type of leukemia. We will explore the therapeutic effects and side effects of JQ1 as well as other candidate epigenetic targets and their respective small molecule inhibitors in our AML PDX model. We will further investigate the potential mechanism by ChIP-seq and RNA-seq. Our studies will provide the theoretical basis for clinical intervention of AML with chromosome -7/del(7q).

染色体异常是复发难治AML的显著特征，其中7/7q缺失发生频率最高，且与预后不良密切相关。课题组首次鉴定了7q上的一个关键抑制基因Mll3(Cancer Cell 2014)，近期我们在染色体17p上又证实了单个基因的缺失或突变不能代表染色体大片段缺失(Nature 2016)。因此，本研究利用NSG小鼠构建7/7q缺失AML的PDX模型，进而鉴定新型治疗靶标，特别是在小鼠模型中初步验证的表观遗传学基因。我们收集了近40例AML病人标本，在NSG小鼠中成功构建了20多例AML PDX模型。前期我们发现表观遗传学异常在7/7q缺失AML发生中有重要作用，针对表观遗传学基因Brd4的抑制剂JQ1对这类白血病有好的干预效果。我们将在PDX模型中验证JQ1和其它候选表观遗传学靶标及对应小分子药物的治疗效果，并利用组学技术研究可能的作用机理。本研究将为探索7/7q缺失AML的临床干预奠定理论基础。

本项目计划围绕“7/7q 缺失AML PDX模型构建及新型治疗靶点的探索”进行研究。首先，成功构建了构建 7/7q 缺失的 AML PDX 模型。其次，探索了新药 XPO1 抑制剂塞利尼索及免疫调节剂泊马度胺对7/7q 缺失 AML PDX 模型中治疗有效。最后，使用 RNA-seq、ChIP-seq、 Western Blot、RT-qPCR 等一系列实验技术阐明上述药物干预 7/7q 缺失AML可能的作用机理。

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