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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

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.

摘要