MAP7在正常核型急性髓系白血病中的预后意义及分子机制

Normal karyotype acute myeloid leukemia (CN-AML) is the largest cytogenetic group of AML. They have strong heterogeneity, however, lack efficient prognostic biomarkers. Using bioinformatic approaches, we have found: (1) Higher expression of MAP7 is associated with poor outcomes in 2 large cohort of CN-AML patients; (2) MAP7's expression is positively correlated with NF-κB pathway; (3) MAP7's expression is negatively correlated with miR-23a and miR-195 that may target MAP7 using prediction software analysis. Based on these above findings, we aim to carry out the following studies: (1) Validating the prognostic value of MAP7 using RQ-PCR in 100 CN-AML patients; (2) Studying how MAP7 effects the biologic behaviors of CN-AML cell lines and the oncogenesis in mice models; (3) Confirming the activating effect of MAP7 for NF-κB pathway; (4) Verifying the inhibition of MAP7 expression from miR-23a and miR-195, and clarifying the epigenetically silent mechanisms of miR-23a and miR-195. Our study will confirm MAP7's significance with clinical prognosis for CN-AML, and establish the theoretical foundation for MAP7 as an indicator to the risk stratification of CN-AML.

正常核型急性髓系白血病(CN-AML)是临床上最多的急性髓系白血病(AML)，其预后异质性极强，且缺乏有效的预后标志物。前期我们利用生物信息学发现：（1）微管结合蛋白7（MAP7）在2个独立的CN-AML数据集中均为预后不良标志物；（2）MAP7和NF-κB信号通路正相关；（3）MAP7和预测能靶向它的miR-23a、miR-195负相关。本课题拟在前期工作基础上进行：（1）定量PCR检测100例CN-AML患者，进一步对MAP7在CN-AML中的临床预后意义进行验证；（2）明确MAP7对CN-AML细胞株生物学行为及小鼠成瘤作用的影响；（3）证实MAP7在CN-AML中活化NF-κB信号通路；（4）阐明miR-23a、miR-195在CN-AML中的沉默机制及其与MAP7表达增高的关系。本课题将最终明确MAP7在CN-AML中的预后意义，为进一步细化CN-AML的危险度分层奠定理论基础。

正常核型急性髓系白血病（CN-AML）临床预后异质性很强，缺乏指导预后的染色体层面的改变，因此亟待寻找新的预后靶标以判断其临床预后。本研究发现MAP7是CN-AML很好的预后标志物，高表达MAP7的CN-AML预后不良，这对CN-AML的危险度分层提供了新的思路；进一步发现高表达MAP7和低表达MAP7的CN-AML携带了特征性的基因、miR-RNA表达谱，这一点有助于寻找MAP7的调控靶点，给靶向治疗提供了方向。总之，本课题的临床问题明确，创新性强，有助于CN-AML危险度分层的细化和其治疗靶标的研发，是一个具有明确临床意义的课题。