The role of EVI1-induced hypermethylation in leukemogenesis.

 描述(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反复出现的体细胞突变导致DNA甲基化异常在癌症中被发现，特别是在髓系恶性肿瘤中，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。DNA甲基化异常背后的分子机制仍然难以捉摸。嗜生态病毒整合-1(EVI1)在白血病发生中的作用已被充分证实。嗜生态病毒整合-1(EVI1)在多种髓系肿瘤中起致癌作用，包括成人MDS和AML。EVI1在10-25%的儿童和青壮年急性髓系白血病(AML)中也有高表达，且与预后中等至不良有关。值得注意的是，EVI1在体内过表达小鼠骨髓细胞可诱导MDS/AML。EVI1过度表达(EVI1+)与AML中异常的高甲基化信号有关。我们最近的研究表明，EVI1激活导致miR-9启动子异常高甲基化，并解除对miR-9介导的FOXO_3途径的调控。与白血病发生相关的是，miR-9表达的恢复在体外逆转了EVI1介导的骨髓生成抑制。在AML患者中，我们发现EVI1的激活与FOX03的表达呈正相关。与miR-9类似，miR124也被EVI1诱导的超甲基化抑制。我们推测，EVI1诱导的DNA高甲基化通过解除对miR-9/miR-124介导的致癌途径的调控，在EVI1诱导的AML中起核心作用。由于EVI1在造血干/祖细胞(HSPC)和白血病启动细胞(LICs)的维持中起关键作用，我们将重点了解EVI1诱导的高甲基化在HSPC向LICs转化中的作用。我们将1)确定EVI1激活如何诱导DNA高甲基化；2)利用动物模型确定miR-9和miR-124在正常造血和EVI1诱导的AML中的作用；3)确定由miR-9和miR124调控的新的致癌途径，并确定这些途径在EVI1诱导的AML中的作用。我们期待我们的研究将为深入了解EVI1激活解除对HSPC自我更新、增殖和分化的调控并导致遗传不稳定性的新的分子机制提供帮助。针对EVI1(+)AML的靶向治疗仍然不可用。我们的研究可能有助于确定更有效的治疗策略 用于通过靶向受EVI1诱导的DNA超甲基化影响的关键分子通路来治疗EVI1(+)AML。

 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.