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：
8657849
负责人：
Jing-Ruey Joanna Yeh
金额：
$ 34.56万
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 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8657849
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 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 screening 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.

描述（由申请人提供）：许多白血病，包括急性骨髓性白血病（AML），是由（1）改变分化和（2）促进多能造血祖细胞增殖的致癌突变引起的。大多数化学疗法靶向大量白血病细胞的增殖，但很少有人靶向多能白血病干细胞的分化缺陷。靶向白血病干细胞分化的疗法的发展受到建模在体外建模癌基因中断的细胞命运决策的困难以及在体内进行高通量小分子筛查的困难。一种模拟癌基因对体内细胞分化的影响的系统，同时还可以实现高通量化学筛查，可以打开靶向白血病干细胞分化的疗法的门。癌基因AML1-ETO（AE）导致造血祖细胞的分化缺陷，从而导致AML患者的粒细胞爆炸细胞积累。 AE在发展斑马鱼中的表达也破坏了造血祖细胞分化，从而导致类似于人类AML患者的粒细胞爆炸细胞的积累。用AE表达斑马鱼进行的2100个小分子的试验屏幕已经确定了三种化合物类别，可阻止AE对造血祖细胞分化的影响。现在提出了一个较大的小分子屏幕，并期望它会发现拮抗AE功能的其他化合物。发现的化合物将经过机械研究，并使用AML的人类细胞和小鼠模型对治疗潜力进行评估。提出了以下特定目的：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。通过利用斑马鱼对疾病建模和小分子筛查的独特能力，该项目将提供有力的工具，用于解剖导致AML的致癌途径，并可能指出有望采用新的化学治疗方法来治疗该疾病。