组蛋白去甲基化酶KDM4A在急性髓细胞白血病中的功能及其机制研究

Recently, the histone demethylase, lysine (K)-specific demethylase 4A (KDM4A), is reported to play a critical role in the regulation of cell proliferation, differentiation and apoptosis, as well as promote tumor cell proliferation. Gene amplification of KDM4A has been associated with prostate, breast, esophagus, and brain cancers. However, the potential molecular mechanisms are yet to be elucidated. Our previous work has defined the differential expression pattern of KDM4A, also known as JMJD2A or JHDM3A, between leukemia stem cells (LSC) and hematopoietic stem cells (HSC) in a mouse model of human MLL-AF9 leukemia. With further study, the expression of KDM4A was up-regulated in bone marrow nucleated cells isolated from patients with de novo and relapsed leukemia, whereas, down-regulated with complete remission. In this project, we intend to comprehensively investigate the distinct function of KDM4A in acute myeloid leukemia, which includes i) evaluating the KDM4A expression in leukemic cells of AML patients and clarifying its prognostic role; ii) manipulating the expression of KDM4A in leukemic cells to study biological characteristics and functions using genetic manipulation and functional experiments; iii) exploring the mechanisms of transcriptional and epigenetic regulation by high-through put detection and bioinformatics analysis; iv) verifying the results obtained from cell lines in animal models and clinical samples. The project will specify the functions and mechanisms of aberrant KDM4A expression in human leukemia and provide evidences for KDM4A as a novel therapeutic target in leukemia therapy.

近年来发现，组蛋白去甲基化酶KDM4A参与调控多种与细胞增殖、分化、凋亡相关基因，促进肿瘤细胞增殖，但机制尚不十分明确。我们前期工作发现，在小鼠白血病模型中，KDM4A基因在白血病干细胞（LSC）和正常造血干细胞（HSC）呈差异性表达；临床标本研究提示，KDM4A基因在急性髓细胞白血病（AML）细胞中表达显著上升，其表达水平变化与AML的发生、缓解和复发呈现一定的相关性。本项目拟进一步扩大临床病例检测研究，从mRNA表达水平及蛋白表达水平分析KDM4A在急性髓细胞白血病发生、缓解和复发中的作用和地位；利用基因操作及相应的功能实验，观察KDM4A表达变化对白血病细胞生物学特性及功能的影响；通过高通量检测和生物信息学分析，明确KDM4A调节白血病细胞功能的基因转录和表观遗传机制；并利用白血病动物模型和临床标本验证机制，为阐明白血病发病机制和发现潜在的治疗靶点奠定实验基础。

近年来发现，组蛋白去甲基化酶KDM4A参与调控多种与细胞增殖、分化、凋亡相关基因，促进肿瘤细胞增殖，但机制尚不十分明确。我们前期工作发现，在小鼠白血病模型中，KDM4A基因在白血病干细胞（LSC）和正常造血干细胞（HSC）呈差异性表达；临床标本研究提示，KDM4A基因在急性髓细胞白血病（AML）细胞中表达显著上升，其表达水平变化与AML的发生、缓解和复发呈现一定的相关性。本项目利用临床病例标本，研究显示KDM4A的高表达是患者预后的不良因素；细胞系水平的研究同样提示，治疗干预下KDM4A的表达下降与白血病细胞的增殖受抑密切相关；在小鼠MLL-AF9白血病研究模型的工作则发现敲除KDM4A移植白血病集落形成，提示KDM4A对维持白血病干细胞的功能起着关键作用。