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:
- 金额:$ 40.6万
- 依托单位:
- 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:
- 关键词:Acute Myelocytic LeukemiaBindingBinding SitesBiological ProcessCellsComplexDNA Sequence RearrangementDataDependenceDevelopmentEnsureEssential GenesGene ExpressionGene Expression RegulationGene MutationGenesGenetic ModelsGenetic TranscriptionGenomic approachGenomicsGrowthHematologic NeoplasmsHematopoiesisHematopoietic stem cellsHumanLeukemic CellLifeMachine LearningMaintenanceMediatingMessenger RNAMethylationModificationMolecularMusOncogenesPathogenesisPathogenicityPathway interactionsPatientsPlayPost-Transcriptional RegulationProtein Binding DomainProteomicsRNARNA BindingRNA methylationRNA-Binding ProteinsReaderRegulationRibosomesRoleSiteTACC3 geneTestingTimeTranscriptbasecrosslinking and immunoprecipitation sequencingdemethylationepitranscriptomegenomic dataimprovedin vivoknock-downleukemialeukemia treatmentleukemic stem cellleukemogenesismembermouse geneticsmouse modelnovelnovel therapeutic interventionpolysome profilingrecruitself-renewalstemstem cell self renewalsuccesstargeted treatmenttranscriptometranscriptome 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
急性髓系白血病(AML)是最常见和最致命的血液系统恶性肿瘤之一
由基因突变和基因组重排引起。急性髓系白血病患者的治愈率还没有
几十年来有了显著的改善。急性髓系白血病发病的分子机制尚不清楚
完全理解。通过使用一种新的机器学习方法来分析公开可用的基因组数据,RNA
结合基序蛋白33(RBM33)是一种RNA结合蛋白,被认为是急性髓系白血病的必需基因。
然而,RBM33的生物学功能尚不清楚。我们的初步研究提供了第一个令人信服的
有证据表明,RBM33在调节m6A RNA去甲基化中具有新的功能。更重要的是,我们
结果表明,RBM33基因敲除显著抑制了人和小鼠白血病的生长和存活
细胞。在分子水平上,我们已经在白血病细胞中确定了RBM33的一个潜在的下游靶点。
ALKBH5被称为m6A mRNA去甲基酶(Eraser),它从RNA中去除m6A甲基化基团。
到目前为止,还不清楚是否需要另一个rna结合蛋白成员来确保
将ALKBH5募集到其信使核糖核酸靶点。我们最近证明了ALKBH5在
AML的开发和维护。我们推测RBM33在骨肉瘤的发病机制中起关键作用。
AML通过调节ALKBH5介导的m6A去甲基化。为了验证这一假设,我们将探讨三个具体的问题
目标。在Aim1中,我们将确定RBM33在调节动态m6A RNA甲基化中的一个新角色。
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《目标3》中,
我们将确定介导RBM33在AML白血病发生中作用的下游通路。
我们将使用小鼠遗传模型以及人类患者衍生的小鼠模型来阐明
RBM33在体内正常造血和白血病发生中的作用,并将结合转录组和
表位转录组分析,以确定关键的下游目标和相关的下游途径
介导RBM33在白血病发生中的作用。我们的研究将揭示RBM33在m6A RNA中的一个新角色
并定义了RBM33在急性髓系白血病发生和发展中的重要性和潜在机制。
维护以及LSC/LIC自我更新。因此,我们项目的成功将极大地推动我们的
了解M6A修饰介导的基因调控的复杂机制
白血病细胞和m6A RNA去甲基化在白血病发生中的关键作用。
项目成果
期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
专利数量(0)
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ALKBH5 介导的 RNA 去甲基化在维持 HSPC 基因组稳定性中的作用
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