Ezh2 in MLL-AF9 mediated acute myeloid leukemia

Ezh2 在 MLL-AF9 介导的急性髓系白血病中的作用

基本信息

批准号：
8884391
负责人：
Tobias Neff
金额：
$ 14.6万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8884391
关键词：
Acute Myelocytic Leukemia Acute leukemia Adult Advisory Committees Affect B-Cell Lymphomas Bioinformatics Biological Assay Bone Marrow Cells Boston Cancer Model Catalytic Domain Cell physiology Cells Child Chromatin Clinical Complex Cultured Cells Cytosine DNA Data Set Development Disease EZH2 gene Embryonic Development Enzymes Epigenetic Process Excision Experimental Hematology Gene Expression Gene Expression Profile Gene Expression Regulation Gene Targeting Gene Transfer Genetic Genomic approach Hematology Hematopoietic stem cells Histones Human Human Cell Line Knockout Mice Laboratories Lead Link Lysine MLLT3 gene Maintenance Malignant Neoplasms Maps Mediating Mentors Mentorship Methylation Methyltransferase Mixed-Lineage Leukemia Modeling Modification Molecular Molecular Profiling Multiprotein Complexes Mus Pathway interactions Patients Pediatric Hematology Pediatric Hospitals Phenotype Physicians Polycomb Population Prognostic Marker Property Reporting Research Role Sampling Scientist Staging Stem cells System Technology Therapeutic Therapeutic Intervention Tissues Training Transplantation anticancer research cancer therapy career cell type collaborative environment dosage genome-wide granulocyte histone modification improved infancy inhibitor/antagonist insight interest leukemia leukemia treatment leukemic stem cell leukemogenesis loss of function macrophage molecular phenotype mouse model novel oncology organ growth overexpression progenitor self-renewal small hairpin RNA small molecule stem stem cell biology tumor tumor progression vector

项目摘要

DESCRIPTION (provided by applicant): Increasing evidence suggests a critical role for epigenetic mechanisms in development, stem cell physiology and cancer. Polycomb Repressive Complex 2-mediated trimethylation of histone 3 on lysine residue 27 (H3K27me3) is catalyzed by the enzyme Enhancer of Zeste 2 (EZH2). Overexpression of EZH2 is correlated with clinical cancer progression in patients and forced expression of EZH2 can contribute to transformation of cultured cells. Inhibition of EZH2 by shRNA strategies has been correlated with decreased proliferative potential in several cancer models. Interestingly, haploinsufficiency for EZH2 has recently been described in human B-cell lymphomas. The functional consequences of EZH2 haploinsufficiency on cellular phenotype have not yet been characterized in experimental cancer models. We propose to study the role of Ezh2 in a genetically defined model of acute leukemia mediated by MLL-AF9 that is well characterized in our laboratory. Genetic loss of Ezh2 in homozygous and/or heterozygous settings will allow us to compare the effects of defined dosages of Ezh2 on tumor phenotype, including complete loss of activity. This technical advance will circumvent limitations associated with shRNA technology and will definitively clarify if Ezh2 is essential for AML. Our system will also allow for detailed characterization of chromatin and gene expression changes associated with loss of Ezh2, thus providing important mechanistic insights. Results obtained in the murine system will be compared with results obtained from the analysis of human cell lines and primary patient samples. The specific aims are: 1: Loss of Function and Forced Expression Studies to Define the Role of Ezh2 in Leukemic Self-Renewal 2: Molecular Characterization of Pathways Affected by Loss of Ezh2 in Murine and Human MLL-AF9 Leukemia Cells Dr. Tobias Neff, a pediatric hematology/oncology fellow at Children's Hospital Boston (CHB) has outlined a 5-year career plan that will build upon his background in clinical hematology/oncology and experimental hematology. Under the co-mentorship of Drs. Scott Armstrong and Stuart Orkin, recognized leaders in leukemia, hematopoietic stem cell biology, and transcriptional gene regulation, he seeks to utilize a definitive biologically relevant mouse model and genomic approaches to study the role of Enhancer of Zeste 2 (Ezh2) in acute myeloid leukemia. Dr. Neff will be mentored by an Advisory Committee of internationally recognized experts in the field. Finally, the plan is ideally carried out in the Division of Hematology/Oncology at Children's Hospital Boston, given its distinguished record for training physician-scientists in a rich and collaborative environment.

描述（由申请人提供）：越来越多的证据表明表观遗传机制在发育，干细胞生理和癌症中的关键作用。 PolyComb抑制性复合物2介导的组蛋白3在赖氨酸残基27上的三甲基化（H3K27me3）是由Zeste 2（EZH2）的酶增强剂催化的。 EZH2的过表达与患者的临床癌症进展相关，EZH2的强迫表达可以有助于培养细胞的转化。 SHRNA策略对EZH2的抑制与几种癌症模型的增殖潜力降低相关。有趣的是，最近在人类B细胞淋巴瘤中描述了EZH2的单倍不足。 EZH2单倍不足在实验癌症模型中尚未表征EZH2单倍性对细胞表型的功能后果。我们建议研究EZH2在由MLL-AF9介导的急性白血病模型中的作用，该模型在我们的实验室中得到很好的特征。纯合子和/或杂合设置中EZH2的遗传丧失将使我们能够比较定义的EZH2剂量对肿瘤表型的影响，包括完全丧失活性。这种技术进步将规避与SHRNA技术相关的限制，并将明确阐明EZH2是否对AML至关重要。我们的系统还将允许对染色质和基因表达变化的详细表征与EZH2丢失相关，从而提供了重要的机械见解。将在鼠系统中获得的结果与通过人类细胞系和原发性患者样品的分析获得的结果进行比较。 The specific aims are: 1: Loss of Function and Forced Expression Studies to Define the Role of Ezh2 in Leukemic Self-Renewal 2: Molecular Characterization of Pathways Affected by Loss of Ezh2 in Murine and Human MLL-AF9 Leukemia Cells Dr. Tobias Neff, a pediatric hematology/oncology fellow at Children's Hospital Boston (CHB) has outlined a 5-year career plan that will build upon his background in clinical血液学/肿瘤学和实验血液学。在Drs的联合统治下。斯科特·阿姆斯特朗（Scott Armstrong）和斯图尔特·奥金（Stuart Orkin），在白血病，造血干细胞生物学和转录基因调控中公认的领导者，他试图利用一种确定的生物学相关的小鼠模型和基因组方法来研究急性肌动型白血病的Zeste 2（ezh2）的作用。 NEFF博士将由该领域的国际认可专家咨询委员会指导。最后，该计划是在波士顿儿童医院的血液学/肿瘤学系中进行的，鉴于其在富裕且协作的环境中培训医师科学家的杰出记录。