The role and mechanism of FTO in leukemogenesis and drug response

FTO在白血病发生和药物反应中的作用和机制

基本信息

批准号：
9285446
负责人：
Jianjun Chen
金额：
$ 38.99万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2017-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9285446
关键词：
11q23 Acute Myelocytic Leukemia Acute Promyelocytic Leukemia Address Adipocytes Animal Model Arsenic Trioxide Basic Science Biological Biological Process Bone Marrow Transplantation Brain Cell Differentiation process Cells Consensus Coupled DNA Modification Process Data Development Differentiation Therapy Disease Drug resistance Eating Epigenetic Process FLT3 gene Fatty acid glycerol esters GTP-Binding Protein alpha Subunits, Gs Gene Targeting Genetic Genetic Transcription Goals Growth Heat-Shock Response Hematopoietic Hematopoietic Neoplasms Human Immunoprecipitation Knock-out Lead Maintenance Malignant Neoplasms Mediating Messenger RNA MicroRNAs Modeling Modification Molecular Mus Mutation NPM1 gene Obesity Oncogenic Pathogenesis Pathologic Pathway interactions Patients Pharmaceutical Preparations Play Proteins RARA gene RNA RNA Splicing RNA Stability RNA immunoprecipitation sequencing RNA methylation RNA, Messenger, Splicing RNA-Protein Interaction Regulation Reporting Research Research Design Resolution Risk stratification Role Signal Transduction Stem cells Study models Technology Tissues Translational Research Translations Tretinoin Untranslated RNA Validation Xenograft procedure base circadian pacemaker crosslink crosslinking and immunoprecipitation sequencing demethylation genome-wide analysis histone modification improved insight interest leukemia leukemogenesis lipid biosynthesis novel novel therapeutics overexpression response self-renewal stem stem-like cell success t(8 21)(q22 q22)targeted treatment transcriptome

项目摘要

PROJECT SUMMARY (ABSTRACT): Background: The identification of FTO as the first N6-methyladenosine RNA demethylase have spurred immense interest in study of the regulatory functions of m6A modifications. Despite the critical impacts of the m6A modifications in various fundamental biological processes, the function (and molecular mechanism) of FTO in cancers, such as acute myeloid leukemia (AML), has yet to be studied. AML is one of the most common and fatal forms of hematopoietic malignancies. Despite the improved risk stratifications and treatment- adapted strategies, >70% of AML patients cannot survive over 5 years due to drug resistance. Thus, it is critical to better understand molecular mechanisms underlying pathogenesis and drug response of AML, which may lead to the development of effective novel therapeutic strategies to treat AML. Our data suggest that FTO likely plays a critical oncogenic role in the pathogenesis of MLL-rearranged AML and in drug response of t(15;17) AML. We show that FTO is highly expressed in AMLs carrying t(11q23)/MLL-rearrangements, t(15;17), NPM1 mutations and/or FLT3-ITD, namely FTO-high AMLs, which are more sensitive to all-trans-retinoic acid (ATRA) and/or arsenic trioxide (ATO) treatment than the other AML subtypes. ATRA/ATO-based differentiation therapy has transformed t(15;17) AML from a highly fatal disease to a highly curable one. However, the role of FTO and the underlying molecular mechanism in the pathogenesis and drug response of FTO-high AMLs are elusive. Objective/Hypothesis: We hypothesize that FTO, as a major m6A eraser, plays a critical role in both pathogenesis and drug response of FTO-high AMLs through epigenetically regulating expression of its targets. Specific Aims: (1) To determine the role of FTO in both development and maintenance of FTO-high AMLs; (2) To identify critical direct targets of FTO and the regulatory mechanism(s) in FTO-high AMLs; and (3) To determine the role and underlying mechanism of FTO in the response of FTO-high AMLs to ATRA and/or ATO treatment. Study Design: 1) We will use the Fto knockout model coupled with mouse bone marrow transplantation (BMT) leukemia models to investigate the pathological function of FTO in both development and maintenance of various subtypes of FTO-high AMLs and in the self-renewal of relevant leukemia stem/initiating cells (LSCs/LICs). 2) We will identify critical direct target genes of FTO by integrating m6A distribution data with FTO-RNA interaction data, and will decipher the molecular mechanism(s) by which FTO post-transcriptionally regulates expression of its direct target genes, followed by functional studies of the top candidate targets of FTO in the pathogenesis of FTO-high AMLs. 3) We will use both mouse BMT leukemia models and patient- derived xeno-transplantation models to determine the role and underlying molecular mechanism of FTO in the response of FTO-high AMLs to ATRA and/or ATO treatment. The critical target genes of FTO and relevant pathways that are responsible for the response of FTO-high AMLs to ATRA and/or ATO treatment will be identified.

项目摘要（摘要）：背景：将FTO鉴定为第一个N6-甲基腺苷RNA脱甲基酶对M6A修饰的调节功能的研究极大的兴趣。尽管有关键的影响 M6A在各种基本生物学过程中修改，该功能（和分子机制）癌症中的FTO，例如急性髓样白血病（AML），尚未研究。 AML是最多的造血恶性肿瘤的常见和致命形式。尽管风险分层和治疗有所改善 - 改编的策略，> 70％的AML患者由于耐药性无法在5年内生存。因此，这很关键为了更好地了解AML的发病机理和药物反应的分子机制，这可能导致开发有效的新型治疗策略来治疗AML。我们的数据表明，FTO可能扮演关键的致癌作用在MLL重升AML的发病机理和T（15; 17）AML的药物反应中。我们证明FTO在携带t（11q23）/mll-renangements的AML中高度表达，t（15; 17），NPM1突变和/或flt3-iTD，即FTO-HIGH-AML，对全反式反激酸（ATRA）和/或更敏感三氧化物（ATO）处理比其他AML亚型。 ATRA/基于ATO的分化疗法具有将T（15; 17）AML从高度致命的疾病转化为高度可治愈的疾病。但是，FTO和 FTO高AML的发病机理和药物反应中的基本分子机制是难以捉摸的。客观/假设：我们假设FTO作为主要的M6A橡皮擦，在两者中都起着至关重要的作用 FTO-HIGH AML通过表观遗传调节其靶标的表达的发病机理和药物反应。具体目的：（1）确定FTO在FTO-HIGH的开发和维护中的作用 amls; （2）确定FTO的关键直接靶标和FTO高AML中的调节机制；（3）确定FTO在FTO高AML对ATRA和/或的响应中的作用和潜在机制 ATO治疗。研究设计：1）我们将使用FTO基因敲除模型和小鼠骨髓移植（BMT）白血病模型研究FTO在发育和维持中的病理功能 FTO高AML的各种亚型以及相关白血病/启动细胞的自我更新（LSC/LICS）。 2）我们将通过将M6A分布数据与 FTO-RNA相互作用数据，并将破译分子机制，然后在转录后FTO。调节其直接靶基因的表达，然后进行功能研究 FTO在FTO高AML的发病机理中。 3）我们将使用小鼠BMT白血病模型和患者 - 派生的异种移植模型，以确定FTO在FTO中的作用和潜在分子机制 FTO高AML对ATRA和/或ATO处理的响应。 FTO和相关的关键靶基因将确定负责FTO-HIGH AML对ATRA和/或ATO处理的响应的途径。