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。

• 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
• 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

 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）：EVI 1诱导的高甲基化在白血病发生中的作用在癌症中，特别是在骨髓恶性肿瘤中，包括急性骨髓性白血病（AML）和骨髓增生异常综合征（MDS），鉴定出越来越多的导致异常DNA甲基化的复发性体细胞突变。异常表观遗传修饰已成为促进白血病发生的关键机制。异常DNA甲基化背后的分子机制仍然难以捉摸。亲嗜性病毒整合-1（EVI 1）在白血病发生中的作用已得到充分证实。亲嗜性病毒整合-1（EVI 1）在多种骨髓肿瘤中发挥致癌作用，包括成人的MDS和AML。在10-25%的儿童和年轻成人急性髓性白血病（AML）中也检测到EVI 1高表达，并且其与中等至不利的预后相关。值得注意的是，在鼠骨髓细胞中EVI 1的过表达在体内诱导MDS/AML。在AML中，EVI 1过表达（EVI 1+）与异常高甲基化特征相关。我们最近的研究表明，EVI 1激活导致miR-9启动子异常甲基化，并使miR-9介导的FOXO 3通路失调。与白血病发生相关，miR-9表达的恢复逆转了体外EVI 1介导的骨髓生成抑制。在AML患者中，我们发现EVI 1激活与FOXO 3表达呈正相关。与miR-9类似，miR 124也被EVI 1诱导的高甲基化抑制。我们推测，EVI 1诱导的DNA高甲基化通过下调miR-9/miR-124介导的致癌通路在EVI 1诱导的AML中发挥核心作用。由于EVI 1在维持造血干/祖细胞（HSPC）和白血病起始细胞（LIC）中起着关键作用，我们将重点了解EVI 1诱导的超甲基化在HSPC转化为LIC中的作用。我们将1）确定EVI 1激活如何诱导DNA高甲基化; 2）使用动物模型确定miR-9和miR-124在正常造血和EVI 1诱导的AML中的作用; 3）鉴定由miR-9和miR-124调控的新致癌通路，并确定这些通路在EVI 1诱导的AML中的作用。我们希望我们的研究将提供新的分子机制的见解EVI 1激活解除自我更新，增殖和分化的HSPCs，并导致遗传不稳定性。EVI 1（+）AML的靶向治疗仍然不可用。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EVI 1诱导的DNA超甲基化影响的关键分子途径治疗EVI 1（+）AML。