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The role and mechanism of METTL3/METTL14-mediated RNA modification in the pathogenesis and drug-resistance of AML

METTL3/METTL14介导的RNA修饰在AML发病及耐药中的作用及机制

基本信息

批准号：
10329928
负责人：
Jianjun Chen
金额：
$ 45.07万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10329928
关键词：
11q23 Acute Myelocytic Leukemia Address Affect Anthracycline Ara-C Basic Science Biological Process Biology Bone Marrow Transplantation Cell Differentiation process Cells Chemoresistance Complex Coupled Cytarabine Cytogenetics Data Data Set Daunorubicin Deposition Development Disease Disease remission Drug resistance FLT3 gene Frequencies Genes Goals Hematopoietic Hematopoietic Neoplasms Hematopoietic stem cells Human In Vitro Knock-in Mouse Knockout Mice Lead Leukemic Cell Life Light MLL-AF9 MLL-rearranged leukemia Maintenance Malignant Neoplasms Mediating Messenger RNA Methyltransferase Modeling Modification Molecular Mus Mutation NPM1 gene Neoadjuvant Therapy Oncogenic Pathogenesis Pathologic Pathway interactions Patients Plant Roots Play Post-Transcriptional Regulation Prognosis Proteins RNA RNA Stability Reader Refractory Regulation Relapse Reporting Research Design Resistance Role Stress Therapeutic Time Tissues Transgenic Organisms Translational Research Translations Transplant Recipients Treatment Failure Validation Xenograft procedure acute myeloid leukemia cell bioprocess cancer type chemotherapy crosslinking and immunoprecipitation sequencing drug relapse in vivo insight leukemia loss of function mouse model mutant novel novel therapeutic intervention novel therapeutics overexpression response ribosome profiling self-renewal side effect stem stem cell self renewal stem-like cell success transcriptome transcriptome sequencing transplant model validation studies virtual

项目摘要

PROJECT SUMMARY (ABSTRACT): Background: N6-methyladenosine (m6A) modification is the most abundant internal modification in eukaryotic messenger RNAs (mRNAs) and plays critical roles in various normal bioprocesses. Evidence is emerging that m6A and the associated machinery also play roles in cancers. Acute myeloid leukemia (AML) is one of the most common and fatal forms of hematopoietic malignancies with distinct cytogenetic (e.g., MLL-rearranged) and molecular (e.g., mutations in FLT3 and NPM1) abnormalities. Over 70% of AML patients cannot be cured by contemporary therapies due to drug resistance and relapse. The leukemia stem/initiating cells (LSCs/LICs) are considered to be the root cause for the treatment failure and relapse of AML. Thus, it is critical to better understand the molecular mechanisms underlying AML pathogenesis, LSC/LIC self-renewal and drug resistance, which may lead to the development of effective novel therapeutic strategies to treat AML. RNA m6A modification is deposited by the METTL3-METTL14 methyltransferase complex (MTC; i.e., writer), and may affect the stability and/or translation efficiency of target mRNAs. We and others have reported that both METTL3 and METTL14 play oncogenic roles in MLL-rearranged AML, but their definitive roles in the development and maintenance of other (i.e., non-MLL- rearranged) subtypes of AMLs and especially in LSC/LIC self-renewal remain elusive. Our unpublished preliminary data imply that METTL3 and METTL14 may also play roles in drug resistance in AML, which warrants further systematic studies. Furthermore, their critical targets in AMLs have yet to be well investigated. Hypothesis: METTL3 and METTL14 play essential oncogenic roles in AML pathogenesis, LSC/LIC maintenance and drug resistance through m6A-dependent regulation of expression of critical target genes. Specific Aims: 1) To determine the roles of METTL3 and METTL14 in the development and maintenance of different subtypes of AMLs, as well as in the self-renewal of relevant LSCs/LICs and normal HSCs; 2) To determine the roles of METTL3 and METTL14 in drug resistance of AMLs; and 3) To decipher the molecular mechanisms underlying the pathological roles of METTL3 and METTL14 in AML development/maintenance, LSC/LIC self-renewal and drug resistance. Study Design: 1) We will use inducible Mettl3 and Mettl14 knockout mouse models coupled with mouse AML models, as well as patient-derived xeno-transplantation (PDX) models, to investigate the roles of METTL3 and METTL14 in development/maintenance of different subtypes of AMLs and self-renewal of LSCs/ LICs and normal hematopoietic stem cells (HSCs). 2) We will conduct both gain- and loss-of-function in vivo studies to determine whether METTL3 and METTL14 play critical roles in drug resistance of AMLs. 3) We will perform PAR- CLIP-seq, m6A-seq, RNA-seq, RNA life-time profiling-seq, and ribosome profiling-seq to identify all direct targets of METTL3 and METTL14 in AMLs and to understand how METTL3 and METTL14 regulate expression of their target RNAs, followed by validation and functional studies of a set of top candidate targets.

项目总结（摘要）：