Discovering chemical tools for acute myelogenous leukemia

发现治疗急性髓性白血病的化学工具

基本信息

批准号：
8248294
负责人：
Jing-Ruey Joanna Yeh
金额：
$ 35.63万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8248294
关键词：
AML1-ETO fusion protein Acute Myelocytic Leukemia Address Binding Biological Biological Models Blast Cell Blood Cell Differentiation process Cell Maturation Cells Chemical Modifier Chemicals Chimeric Proteins Chromosomal translocation Clinical Complex Core-Binding Factor Defect Development Dicumarol Disease Disease model Down-Regulation Embryo Enhancers Erythroid Cells Erythropoiesis Genes Granulopoiesis Hematopoietic Hematopoietic stem cells Histone Deacetylase Inhibitor Human In Vitro Lead Mediating Modeling Molecular Abnormality Mutate Mutation Oncogenes Oncogenic PTGS2 gene Pathway interactions Patients Phenotype Play Research Role Screening procedure Signal Pathway Techniques Testing Therapeutic Transgenic Organisms Up-Regulation Validation Zebrafish base chemical genetics chemotherapy design disease phenotype drug candidate expectation follow-up functional restoration fusion gene granulocyte in vivo killings leukemia leukemic stem cell leukemogenesis mouse model new therapeutic target novel therapeutics promoter public health relevance research study small molecule stem cell differentiation therapeutic target therapy development tool

项目摘要

DESCRIPTION (provided by applicant): Many leukemias, including acute myelogenous leukemia (AML), are caused by oncogenic mutations that (1) alter differentiation and (2) promote proliferation of multipotent hematopoietic progenitor cells. Most chemotherapies target proliferation of the bulk leukemia cells, but few target the differentiation defects of multipotent leukemia stem cells. Development of therapies that target leukemia stem cell differentiation has been hindered by the difficulties of modeling oncogene-disrupted cell fate decisions in vitro and the difficulties of conducting high-throughput small molecule screens in vivo. A system that models the effects of oncogenes on cell differentiation in vivo while also enabling high-throughput chemical screening could open the door to therapies that target leukemia stem cell differentiation. The oncogene AML1-ETO (AE) causes a differentiation defect in hematopoietic progenitor cells that leads to accumulation of granulocytic blast cells in AML patients. Expression of AE in developing zebrafish also disrupts hematopoietic progenitor cell differentiation, leading to accumulation of granulocytic blast cells resembling those from human AML patients. A pilot screen of 2100 small molecules conducted with AE- expressing zebrafish has identified three compound classes that block the effects of AE on hematopoietic progenitor cell differentiation. A larger small molecule screen is now proposed, with the expectation that it will discover additional compounds that antagonize AE function. Compounds discovered will be subjected to mechanistic studies and evaluated for therapeutic potential using human cells and mouse models of AML. The following specific aims are proposed: Aim 1. Screening for additional AE antagonists. Aim 2. Elucidating the mechanisms by which the AE antagonists suppress AE function. Aim 3. Validating the therapeutic utility of the AE antagonists. By exploiting the unique capabilities of the zebrafish for disease modeling and small molecule screening, the proposed project will provide powerful tools for dissecting the oncogenic pathways leading to AML and may point to promising new chemotherapeutic approaches for treating the disease. PUBLIC HEALTH RELEVANCE: Most chemotherapies for leukemia are designed to kill rapidly dividing cells, but they do not address the defects in cellular maturation that are a major contributor to the development of leukemia. This project will test thousands of potential drug candidates to discover those that can reverse the cell maturation defects in cells containing a common leukemia-causing gene. The primary objective of these studies is discovery and validation of new therapeutic techniques for treating leukemia.

描述（由申请人提供）：许多白血病，包括急性髓性白血病（AML），是由致癌突变引起的，这些突变（1）改变分化，（2）促进多能造血祖细胞增殖。大多数化疗针对的是大量白血病细胞的增殖，但很少针对多能白血病干细胞的分化缺陷。体外对癌基因破坏的细胞命运决定进行建模的困难以及在体内进行高通量小分子筛选的困难阻碍了针对白血病干细胞分化的疗法的开发。一个模拟癌基因对体内细胞分化影响的系统，同时还能进行高通量化学筛选，可以为针对白血病干细胞分化的治疗打开大门。癌基因 AML1-ETO (AE) 会导致造血祖细胞分化缺陷，导致 AML 患者粒细胞母细胞积聚。发育中的斑马鱼中 AE 的表达也会破坏造血祖细胞的分化，导致类似于人类 AML 患者的粒细胞母细胞的积累。使用表达 AE 的斑马鱼对 2100 种小分子进行了初步筛选，确定了三类化合物，可以阻断 AE 对造血祖细胞分化的影响。现在提出了更大的小分子筛选，期望能发现更多拮抗 AE 功能的化合物。发现的化合物将接受机制研究，并使用人类细胞和 AML 小鼠模型评估其治疗潜力。提出以下具体目标：目标 1. 筛选其他 AE 拮抗剂。目标 2. 阐明 AE 拮抗剂抑制 AE 功能的机制。目标 3. 验证 AE 拮抗剂的治疗效用。通过利用斑马鱼进行疾病建模和小分子筛选的独特能力，拟议的项目将为剖析导致 AML 的致癌途径提供强大的工具，并可能为治疗该疾病指出有前途的新化疗方法。公共卫生相关性：大多数白血病化疗旨在杀死快速分裂的细胞，但它们并没有解决细胞成熟的缺陷，而细胞成熟的缺陷是导致白血病发展的主要因素。该项目将测试数千种潜在的候选药物，以发现那些可以逆转含有常见白血病致病基因的细胞的细胞成熟缺陷的药物。这些研究的主要目的是发现和验证治疗白血病的新治疗技术。