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.
Acute myeloid leukemia (AML) is the most common hematological malignant disease. Despite the role of EVI1 in AML being well established, there are no targeted therapies available for AML with high expression of EVI1. The proposed research will elucidate a molecular mechanism by which EVI1 induces the development of AML by deregulating the expression of microRNAs. This study will advance our knowledge and understanding of molecular basis of AML, potentially leading to the identification of new effective therapeutic strategies for the treatment of AML with activation of EVI1.
| Li, Liping; Sheng, Yue; Li, Wenshu et al. (2017) ?-Catenin Is a Candidate Therapeutic Target for Myeloid Neoplasms with del(5q). Cancer Res 77:4116-4126 |
