The role of EVI1-induced hypermethylation in leukemogenesis.

EVI1 诱导的高甲基化在白血病发生中的作用。

基本信息

批准号：
9460543
负责人：
Zhijian Qian
金额：
$ 16.6万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-01 至 2018-08-06
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9460543
关键词：
Aberrant DNA Methylation Acute Myelocytic Leukemia Adult Adult Acute Myeloblastic Leukemia Affect Animal Model Bone Marrow Cells CD34 gene Cell Line Cell Proliferation Cells Childhood Chromatin Chromatin Remodeling Factor DNA DNA Methylation DNMT3B gene DNMT3a Development Disease Down-Regulation Dysmyelopoietic Syndromes Ectopic Expression Epigenetic Process Evolution FOXO3A gene Genes Genetic Goals HDAC1 gene Hematopoiesis Hematopoietic Hematopoietic stem cells Human Hypermethylation In Vitro Knowledge Lead Maintenance Malignant - descriptor Malignant Neoplasms Mediating MicroRNAs Modification Molecular Multiprotein Complexes Mus Myelogenous Myelopoiesis Myeloproliferative disease Neoplastic Processes Oncogenic Pathogenesis Pathway interactions Patients Phenotype Phosphotransferases Play Recurrence Research Role Somatic Mutation Treatment Efficacy Up-Regulation Virus Integration Work base in vivo insight kinase inhibitor leukemia leukemogenesis molecular mechanics mouse model neoplastic novel outcome forecast overexpression promoter proto-oncogene protein pim public health relevance recruit restoration self-renewal targeted treatment treatment strategy young adult

项目摘要

DESCRIPTION (provided by applicant): The role of EVI1-induced hypermethylation in leukemogenesis A growing number of recurrent somatic mutations that lead to aberrant DNA methylation are identified in cancer and specifically myeloid malignancies, including Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS). Aberrant epigenetic modification has emerged as a key mechanism that promotes leukemogenesis. The molecular mechanisms behind aberrant DNA methylation remain elusive. The role of Ecotropic Virus Integration-1 (EVI1) in leukemogenesis has been well established. Ecotropic virus integration-1 (EVI1) plays an oncogenic role in a variety of myeloid neoplasms, including MDS and AML in adults. EVI1 high expression is also detected in 10-25% of pediatric and young adult Acute Myeloid Leukemia (AML), and it is associated with an intermediate to unfavorable prognosis. Notably, overexpression of EVI1 in murine bone marrow cells in vivo induces MDS/AML. EVI1 overexpression (EVI1+) has been associated with an aberrant hypermethylation signature in AML. Our recent studies revealed that EVI1 activation resulted in aberrant hypermethylation of miR-9 promoter and deregulates the miR-9-mediated FOXO3 pathway. Of relevance to leukemogenesis, restoration of miR-9 expression reversed EVI1-mediated suppression of myelopoiesis in vitro. In the AML patients, we found that EVI1 activation is positively associated with FOXO3 expression. Similar to miR-9, miR124 is also inhibited by EVI1-induced hypermethylation. We hypothesize that EVI1-induced DNA hypermethylation plays a central role in EVI1-induced AML through deregulating the miR-9/miR-124-mediated oncogenic pathways. As EVI1 plays a critical role in maintenance of hematopoietic stem/progenitor cells (HSPCs) and leukemia-initiating cells (LICs), we will focus on understanding the role of EVI1-induced hypermethylation in transformation of HSPCs into LICs. We will 1) determine how EVI1 activation induces DNA hypermethylation; 2) determine the role of miR-9 and miR-124 in normal hematopoiesis and EVI1-induced AML using animal models; 3) identify novel oncogenic pathways that regulated by miR-9 and miR124 and determine the role of these pathways in EVI1-induced AML. We expect that our studies will provide insights into the novel molecular mechanisms by which EVI1 activation deregulates self-renewal, proliferation and differentiation of HSPCs and causes genetic instability. The targeted therapy for EVI1(+) AML is still unavailable. Our studies likely lead to the identification of more effective therapeutic strategies for the treatment of EVI1(+) AML by targeting the critical molecular pathways that are affected by EVI1-induced DNA hypermethylation.

描述（由申请人提供）：EVI1 诱导的高甲基化在白血病发生中的作用越来越多的复发性体细胞突变导致异常 DNA 甲基化，在癌症和特别是骨髓恶性肿瘤中被发现，包括急性髓系白血病 (AML) 和骨髓增生异常综合征 (MDS) ）。异常的表观遗传修饰已成为促进白血病发生的关键机制。生态性病毒整合 1 (EVI1) 在白血病发生中的作用已得到充分证实，在多种骨髓肿瘤中发挥致癌作用，包括成人 MDS 和 AML。在 10-25% 的儿童和年轻成人急性髓系白血病 (AML) 中也检测到表达，并且它与中度至不利的疾病相关值得注意的是，EVI1 在体内的小鼠骨髓细胞中过度表达会导致 MDS/AML（EVI1+）与 AML 中的异常高甲基化特征相关。启动子并解除对 miR-9 介导的 FOXO3 通路的调节，与白血病发生相关，miR-9 表达的恢复被逆转。 EVI1 介导的体外骨髓生成抑制，我们发现 EVI1 激活与 FOXO3 表达呈正相关，与 miR-9 类似，miR124 也受到 EVI1 诱导的 DNA 高甲基化的抑制。 EVI1 通过解除 miR-9/miR-124 介导的致癌途径在 EVI1 诱导的 AML 中发挥核心作用。为了了解 EVI1 在维持造血干/祖细胞 (HSPC) 和白血病起始细胞 (LIC) 中的作用，我们将重点了解 EVI1 诱导的高甲基化在 HSPC 转化为 LIC 中的作用，我们将 1) 确定 EVI1 激活如何诱导 DNA。 2) 使用动物模型确定 miR-9 和 miR-124 在正常造血和 EVI1 诱导的 AML 中的作用； 3) 确定受 miR-9 和 miR124 调节的新致癌途径，并确定这些途径在 EVI1 诱导的 AML 中的作用。我们希望我们的研究将为 EVI1 激活解除自我更新、增殖调节的新分子机制提供见解。 EVI1(+) AML 的靶向治疗仍然无法实现，我们的研究可能会导致更有效的治疗策略的确定。通过靶向受 EVI1 诱导的 DNA 高甲基化影响的关键分子途径来治疗 EVI1(+) AML。