权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Functional and Translational Epigenomics of Acute Lymphoblastic Leukemia

急性淋巴细胞白血病的功能和转化表观基因组学

基本信息

批准号：
10115629
负责人：
MICHAEL L CLEARY
金额：
$ 36.72万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-03-01 至 2024-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10115629
关键词：
Acute Lymphocytic Leukemia Address Adult B-Cell Acute Lymphoblastic Leukemia B-Lymphocytes Child Chromatin Collection Custom Dasatinib Data Dependence Disease Epigenetic Process Foundations Genes Genetic Genetic Transcription Genomic approach Genomics Individual Libraries Methods Modeling Molecular Morbidity - disease rate Oncogenic Pathogenesis Pathologic Pathway interactions Patients Pharmacology Phosphotransferases Protein Tyrosine Kinase Proteins Reader Regulatory Pathway Resistance Resistance development Role SYK gene Signal Pathway TCF3 gene Therapeutic Tyrosine Kinase Inhibitor ZAP-70 Gene acute lymphoblastic leukemia cell base effective therapy epigenome epigenomics functional genomics genome-wide histone methylation inhibitor/antagonist kinase inhibitor leukemia leukemogenesis mortality neoplastic novel pre-B cell receptor preclinical efficacy preclinical study programs prospective resistance mechanism response small hairpin RNA targeted treatment therapeutic target transcription factor transcriptome treatment response validation studies whole genome

项目摘要

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.

项目总结