The Novel Role and Mechanism of RBM33 in Leukemogenesis

RBM33 在白血病发生中的新作用和机制

基本信息

批准号：
10343898
负责人：
Zhijian Qian
金额：
$ 40.6万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-17 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10343898
关键词：
Acute Myelocytic Leukemia Binding Binding Sites Biological Process Cells Complex DNA Sequence Rearrangement Data Dependence Development Ensure Essential Genes Gene Expression Gene Expression Regulation Gene Mutation Genes Genetic Models Genetic Transcription Genomic approach Genomics Growth Hematologic Neoplasms Hematopoiesis Hematopoietic stem cells Human Leukemic Cell Life Machine Learning Maintenance Mediating Messenger RNA Methylation Modification Molecular Mus Oncogenes Pathogenesis Pathogenicity Pathway interactions Patients Play Post-Transcriptional Regulation Protein Binding Domain Proteomics RNA RNA Binding RNA methylation RNA-Binding Proteins Reader Regulation Ribosomes Role Site TACC3 gene Testing Time Transcript base crosslinking and immunoprecipitation sequencing demethylation epitranscriptome genomic data improved in vivo knock-down leukemia leukemia treatment leukemic stem cell leukemogenesis member mouse genetics mouse model novel novel therapeutic intervention polysome profiling recruit self-renewal stem stem cell self renewal success targeted treatment transcriptome transcriptome sequencing

Acute Myelocytic Leukemia Binding Binding Sites Biological Process Cells Complex DNA Sequence Rearrangement Data Dependence Development Ensure Essential Genes Gene Expression Gene Expression Regulation Gene Mutation Genes Genetic Models Genetic Transcription Genomic approach Genomics Growth Hematologic Neoplasms Hematopoiesis Hematopoietic stem cells Human Leukemic Cell Life Machine Learning Maintenance Mediating Messenger RNA Methylation Modification Molecular Mus Oncogenes Pathogenesis Pathogenicity Pathway interactions Patients Play Post-Transcriptional Regulation Protein Binding Domain Proteomics RNA RNA Binding RNA methylation RNA-Binding Proteins Reader Regulation Ribosomes Role Site TACC3 gene Testing Time Transcript base crosslinking and immunoprecipitation sequencing demethylation epitranscriptome genomic data improved in vivo knock-down leukemia leukemia treatment leukemic stem cell leukemogenesis member mouse genetics mouse model novel novel therapeutic intervention polysome profiling recruit self-renewal stem stem cell self renewal success targeted treatment transcriptome transcriptome sequencing

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项目摘要

Abstract Acute myeloid leukemia (AML) is one of the most common and fatal forms of hematological malignancies caused by gene mutations and genomic rearrangements. The cure rates for AML patients have not significantly improved for decades. The molecular mechanisms underlying the pathogenesis of AML are not fully understood. By analysis of publicly available genomic data using a new machine learning approach, RNA Binding Motif Protein 33 (RBM33), an RNA binding protein, is identified as an essential gene in AML. However, the biological function of RBM33 is unknown yet. Our preliminary studies provide the first compelling evidence suggesting a novel function of RBM33 in regulating m6A RNA demethylation. More importantly, we showed that RBM33 knockdown significantly inhibited growth and survival of human and mouse leukemia cells. At a molecular level, we have identified a potential downstream target of RBM33 in leukemia cells. ALKBH5 is known as an m6A mRNA demethylase (Eraser), which removes m6A methylated groups from RNA. To date, it remains unknown whether another member of RNA binding proteins is required for ensuring recruitment of ALKBH5 to its mRNA targets. We have recently demonstrated that ALKBH5 has a critical role in AML development and maintenance. We hypothesize that RBM33 plays a critical role in the pathogenesis of AML by regulating ALKBH5-mediated m6A demethylation. To test this hypothesis, we will pursue three specific aims. In Aim1, we will determine a novel role of RBM33 in regulation of dynamic m6A RNA methylation in leukemia cells. In Aim2, we will investigate the role of Rbm33 in AML development and maintenance. In Aim 3, we will determine the downstream pathway that mediates the function of RBM33 in leukemogenesis in AML. We will employ both mouse genetic models as well as human patient-derived mouse models to elucidate the role of RBM33 in normal hematopoiesis and leukemogenesis in vivo, and will combine transcriptome and epitranscriptome analysis to identify the key downstream targets and associated downstream pathways that mediate the role of RBM33 in leukemogenesis. Our studies will uncover a novel role of RBM33 in m6A RNA modification, and define the importance and underlying mechanisms of RBM33 in AML development and maintenance as well as LSC/LIC self-renewal. Thus, the success of our project will significantly advance our understanding of the complex mechanisms underlying the m6A modification-mediated gene regulation in leukemia cells and the critical role of m6A RNA demethylation in leukemogenesis.

抽象的急性髓样白血病（AML）是最常见和致命的血液恶性肿瘤形式之一由基因突变和基因组重排引起。 AML患者的治愈率尚未数十年来大大改善。 AML发病机理下的分子机制不是完全理解。通过使用新的机器学习方法分析公开可用的基因组数据，RNA 结合基序蛋白33（RBM33）（RNA结合蛋白）被鉴定为AML中的必需基因。但是，RBM33的生物学功能尚不清楚。我们的初步研究提供了第一个引人注目的证据表明，RBM33在调节M6a RNA脱甲基化方面具有新的功能。更重要的是，我们结果表明，RBM33敲低显着抑制了人类和小鼠白血病的生长和存活细胞。在分子水平上，我们已经确定了白血病细胞中RBM33的潜在下游靶标。 ALKBH5被称为M6A mRNA脱甲基酶（橡皮擦），它去除了RNA中去除M6A甲基化基团。迄今为止，尚不清楚RNA结合蛋白的另一个成员是否需要将ALKBH5募集到其mRNA靶标。我们最近证明了Alkbh5在 AML开发和维护。我们假设RBM33在通过调节ALKBH5介导的M6A脱甲基化，AML。为了检验这一假设，我们将追求三个特定的目标。在AIM1中，我们将确定RBM33在调节动态M6A RNA甲基化中的新作用白血病细胞。在AIM2中，我们将研究RBM33在AML开发和维护中的作用。在AIM 3中，我们将确定介导RBM33在AML中的白血病发生功能的下游途径。我们将使用小鼠遗传模型以及人类的患者衍生的小鼠模型来阐明 RBM33在正常造血和体内白血病发生中的作用，将结合转录组和表参考组分析以识别下游目标和相关下游途径的关键。介导RBM33在白血病中的作用。我们的研究将发现RBM33在M6A RNA中的新作用修改，并定义RBM33在AML开发中的重要性和潜在机制维护以及LSC/LIC自我更新。因此，我们项目的成功将大大推动我们的了解M6A修饰介导的基因调节的复杂机制白血病细胞和M6a RNA脱甲基化在白血病发生中的关键作用。