Functional and Translational Epigenomics of Acute Lymphoblastic Leukemia

项目总结 急性淋巴细胞性白血病(ALL)是一种异质的疾病集合，具有 不同的遗传来源，而且越来越明显的是，有效的治疗必须是 根据每个患者疾病的个别分子特征进行定制。为了推进这一进程 范式，这一应用集中在致病和反应的表观遗传机制上 到所有的靶向治疗。研究集中在一种独特的基因亚型上，表达E2a- Pbx1，一种嵌合转录因子，在50%的ALL中是主要的致癌驱动因素 选择性激活前B细胞受体信号通路(Pre-bcr+)及对 临床前研究中的酪氨酸激酶抑制。尽管对激活信号的抑制 通路是一种很有前途的治疗策略，但随着肿瘤的发展而变得复杂。 通过各种机制产生抗性。其中，主要的表观遗传学改变是 最近观察到的重要的潜在病理机制，驱动可塑性的 肿瘤状态和治疗反应。在AIM 1中，高通量的全基因组“组学” 将使用方法来阐明E2a-Pbx1所属的染色质景观 细胞，使表观基因组与转录组相关，识别错误调节的靶基因，以及 明确它们在白血病发病机制中的作用。在目标2中，初步确定了 依赖于E2A-Pbx1和所有人都需要的研究将进一步确定特征和 利用遗传学和药理学询问病理作用和治疗潜力 方法：研究方法。在目标3中，发现了抵抗激酶抑制的表观遗传学机制 使用基于超复合体的功能基因组学方法进行广泛的初步研究 ShRNA文库筛选将进一步用于前瞻性询问靶向治疗 以达沙替尼耐药为模型的Pre-BCR+ALL的反应。已确定的监管因素 以及可用特定抑制剂进行分子治疗的代偿性耐药途径 靶向染色质相关蛋白将与激酶抑制剂结合进行评估 具有协同增效和抗药性改善作用。这些研究将进一步描述 所有细胞对特定表观遗传效应器的依赖，定义了它们在不同 转录和信号通路，有助于所有的发病机制，并证明他们的 展望作为治疗靶点。

Project summary Acute lymphoblastic leukemia (ALL) represents a heterogeneous collection of diseases with diverse genetic origins, and it is increasingly apparent that effective treatments must be customized to the individual molecular features of each patient’s disease. To advance this paradigm, this application focuses on the epigenetic mechanisms of pathogenesis and response to targeted therapy in ALL. Studies focus on a distinctive genetic subtype that expresses E2A- PBX1, a chimeric transcription factor that is the major oncogenic driver in 50% of ALL with selective activation of the pre-B-cell receptor signaling pathway (pre-BCR+) and response to tyrosine kinase inhibition in preclinical studies. Although inhibition of activated signaling pathways is a promising therapeutic strategy in ALL, it is complicated by the development of resistance through a variety of mechanisms. Among these, primary epigenetic alterations are recently observed as important underlying pathologic mechanisms that drive the plasticity of the neoplastic state and therapeutic response. In Aim 1, a high throughput genome-wide “omics” approach will be used to elucidate the chromatin landscape subordinate to E2A-PBX1 in ALL cells, correlate the epigenome with the transcriptome, identify mis-regulated target genes, and define their roles in leukemia pathogenesis. In Aim 2, the kinome identified in preliminary studies to be dependent on E2A-PBX1 and required for ALL will be further characterized and interrogated for pathologic roles and therapeutic potential using genetic and pharmacologic methods. In Aim 3, epigenetic mechanisms of resistance to kinase inhibition identified in extensive preliminary studies using a functional genomics approach based on ultracomplex shRNA library screens will be further characterized to prospectively interrogate targeted therapy response in pre-BCR+ ALL using dasatinib resistance as a model. Identified regulatory factors and compensatory resistance pathways amenable to molecular therapy with specific inhibitors targeting chromatin-associated proteins will be evaluated in combination with kinase inhibitors for synergistic efficacy and resistance amelioration. These studies will further characterize the dependence of ALL cells on specific epigenetic effectors, define their roles in various transcriptional and signaling pathways that contribute to ALL pathogenesis, and credential their prospects as therapeutic targets.