Define the oncogenic role of METTL3 in the pathogenesis of chronic lymphocytic leukemia
Define the oncogenic role of METTL3 in the pathogenesis of chronic lymphocytic leukemia
批准号:
10717803
负责人:
Lili Wang
金额:
$55.62万
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-07-01 至 2028-06-30
关键词:
AddressAdoptive TransferAutomobile DrivingB-LymphocytesBiologyCRISPR screenCell LineCell ProliferationCellsChemotherapy-Oncologic ProcedureChronic Lymphocytic LeukemiaClinicalClinical TrialsCountryDataData SetDefectDepositionDevelopmentDiseaseDisease ProgressionEssential GenesGenesGenetic TranscriptionGrowthHematologic NeoplasmsHematopoietic stem cellsIn VitroInterleukinsKnock-outKnockout MiceKnowledgeMaintenanceMalignant - descriptorMalignant NeoplasmsMessenger RNAMethyltransferaseModelingModificationMolecularMusMutationOncogenesOncogenicOralOutcomePathogenesisPathway interactionsPatientsPharmacologic SubstancePlayPost-Transcriptional RegulationPrognosisPrognostic MarkerProliferatingProteinsProteomeProteomicsRNARNA SplicingRegimenRegulationReportingRoleSamplingSiteSpliceosomesTechnologyTranscriptTranslationsTreatment ProtocolsUp-Regulationadult leukemiacancer therapychemotherapychronic lymphocytic leukemia celldesignexperimental studygenome editinggenome-wideimprovedin vivoindependencyinhibitorinsightmouse modelnovelnovel therapeutic interventionnovel therapeuticsoverexpressionposttranscriptionalpredictive markerprotein complexprotein expressionribosome profilingsmall molecule inhibitortargeted treatmenttherapeutic targettherapeutically effectivetranscription factortranscriptometranscriptome sequencing
中文摘要
项目摘要
尽管化疗有所改进,侵袭性慢性淋巴细胞白血病(CLL)仍无法治愈
养生法和靶向治疗。更好地理解侵袭性CLL的生物学基础有望
设计新的疗法。
我们最近发现,高剪接体复杂蛋白的表达会导致RNA的异常剪接,即
与侵袭性疾病相关,并可作为慢性淋巴细胞性白血病预后不良的独立预测标志。
强调RNA剪接失调是侵袭性CLL的基础。通过整合的转录组和
对正常和原代CLL B细胞进行蛋白质组分析,我们发现了一种RNA甲基转移酶METTL3
在mRNA上沉积N6-甲基腺苷(M6A)修饰,被强烈暗示为RNA的关键调节因子
CLL中的拼接。METTL3是一种在CLL中高表达的蛋白,与不良的临床预后有关,并且
与剪接因子蛋白表达显著相关。此外,有效的小分子抑制剂
METTL3已经被开发出来,并在血液系统恶性肿瘤中显示出良好的效果。通过以下方式治疗
METTL3抑制剂导致CLL细胞生长缺陷,降低RNA剪接因子蛋白表达。
此外,我们还获得了METTL3过度表达是致癌作用的证据,这与IL-3的非依赖性有关
在BA/F3细胞系模型中。根据这些初步数据,我们假设METTL3可能作为一种
癌基因,并通过调节RNA剪接网络,驱动CLL的发生发展,使
它是治疗侵袭性CLL的潜在靶点。为了解决这一假设,我们建议研究METTL3
是使用小鼠模型开发和维护CLL所必需的(目标1)。我们将剖析
慢性淋巴细胞性白血病中RNA剪接网络靶点的分子机制及其意义
受METTL3(目标2)调控。此外,我们将确定METTL3是否是一个可行的治疗靶点
治疗侵袭性CLL和如果同时靶向METTL3和RNA剪接调控网络具有协同作用
对CLL的影响(目标3)。
总的来说,本申请中提出的实验结果将把METTL3确立为CLL
癌基因,阐明METTL3调节的靶转录本上的m6A修饰促进和
维持CLL,并评估侵袭性CLL的新治疗方法。
英文摘要
Project Summary
Aggressive chronic lymphocytic leukemia (CLL) remains incurable despite with improved chemotherapy
regimens and targeted therapies. Better understanding of the biology underlying aggressive CLL is expected to
design novel therapies.
We recently discovered that high spliceosome complex protein expression results in aberrant RNA splicing, is
associated with aggressive disease and serves as an independent predictive marker for poor prognosis in CLL,
highlighting RNA splicing dysregulation underlies aggressive CLL. Through an integrated transcriptome and
proteome analysis on normal and primary CLL B cells, we discovered that METTL3, an RNA methyltransferase
that deposits N6-methyladenosine (m6A) modification on mRNA, is strongly implicated as a key regulator for RNA
splicing in CLL. METTL3 is a highly expressed protein in CLL, associated with poor clinical outcome, and
significantly correlated with splicing factor protein expression. Moreover, efficacious small molecule inhibitors of
METTL3 have been developed and have shown promising results in hematological malignancy. Treatment with
METTL3 inhibitor results in growth defect in CLL cell lines and decreases RNA splicing factor protein expression.
Moreover, we have obtained evidence that METTL3 overexpression is oncogenic by rending IL-3 independency
in Ba/F3 cell line model. Based on these preliminary data, we hypothesize that METTL3 potentially acts as an
oncogene and drives the onset and progression of CLL through the regulation of RNA splicing network, making
it a potential target for treating aggressive CLL. To address this hypothesis, we propose to investigate METTL3
is required for both development and maintenance of CLL using murine models (Aim 1). We will dissect the
molecular mechanism underlying the targets of RNA splicing network in CLL and understand how they are
regulated by METTL3 (Aim 2). Moreover, we will determine whether METTL3 is a viable therapeutic target in
treating aggressive CLL and if targeting both METTL3 and RNA splicing regulatory network has a synergistic
effect in CLL (Aim 3).
Collectively, the results of the experiments proposed in this application will establish METTL3 as an CLL
oncogene, elucidate the m6A-modification on target transcripts that modulated by METTL3 to promote and
maintain CLL, and evaluate a new therapeutic approach for aggressive CLL.
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会议论文
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海外基金