Understanding resistance mechanisms to protein arginine methyltransransferase Inhibitors in Lymphoma
了解淋巴瘤对蛋白精氨酸甲基转移酶抑制剂的耐药机制
基本信息
- 批准号:10668754
- 负责人:
- 金额:$ 71.39万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-03-13 至 2028-02-29
- 项目状态:未结题
- 来源:
- 关键词:3&apos Untranslated RegionsAccelerationAdultAdvanced Malignant NeoplasmAntibodiesArginineAutomobile DrivingB-Cell LymphomasB-LymphocytesBCL-2 ProteinBCL2 geneBindingBinding ProteinsBiologyCRISPR screenCell LineCell physiologyCellsClinicClinicalCommunicationDataDependenceDiseaseEnzymesEpigenetic ProcessFailureFamilyGenesGeneticGrowthHematologic NeoplasmsHistonesHumanImpairmentLaboratoriesLymphomaLymphoma cellLymphomagenesisLysineMYC Family ProteinMalignant NeoplasmsMediatingMediatorMessenger RNAMethylationModalityModificationMusMutationNatureNon-Hodgkin&aposs LymphomaOncogenicOncoproteinsOutcomePathogenesisPatientsPlayPost-Translational Protein ProcessingProliferatingProtein FamilyProtein-Arginine N-MethyltransferaseProteinsPublishingRNA Recognition MotifRNA-Binding ProteinsRecurrenceResistanceRoleSamplingSiteSolid NeoplasmSystemTherapeuticTranslationsUp-Regulationcell growthgenome-wideimprovedin vivoinhibitorinhibitor therapylarge cell Diffuse non-Hodgkin&aposs lymphomaleukemialoss of functionmolecular targeted therapiesmouse modelmutantnew therapeutic targetnon-histone proteinnovelnovel therapeutic interventionoverexpressionprogramsprotein expressionrelapse patientsresistance mechanismresponsesmall hairpin RNAstemstem cellstargeted treatmenttechnological innovationtranscriptometranslatometumortumor eradication
项目摘要
PROJECT SUMMARY/ABSTRACT
Non-Hodgkin’s lymphoma (NHL) is among the most common cancers and despite current therapies many
patients relapse from their disease. Recent discoveries have implicated epigenetic mechanisms and non-
classical oncogenic programs as dysregulated in patients with B-cell lymphoma. Protein arginine
methyltransferase-5 (PRMT5), the major enzyme responsible for the arginine symmetric dimethylation of
histones and non-histone proteins, plays an important role in lymphomagenesis, controlling the growth of
transformed B cells. PRMT5 is overexpressed in lymphoma and may represent a novel therapeutic target for
this disease. In order to assess what regulators drive resistance, we performed a genome wide CRISPR screen.
Surprisingly, we uncovered the RNA binding protein MUSASHI2 (MSI2) as the top hit. MSI2 is an RNA binding
protein that has been implicated as a stem related protein that is the most highly expressed in the most
aggressive cancers but its role in B-cell lymphoma is not known. Our preliminary data suggests that MSI2 is
highly expressed in lymphomas and reduction reduces proliferation which is further reduced by PRMT5 inhibition.
We also discovered new post-translational modifications mediated by PRMT1 and PRMT5 in B-cell lymphoma
and demonstrated a functional requirement for these newly discovered modifications. We propose to study this
new PRMT-MSI2 axis in driving lymphomagenesis using genetic mouse models, human lymphoma cell lines
and patient samples. Furthermore, we utilize technological innovations to study direct MSI2 targets and the
mechanism for how MSI2 mediates resistance to PRMT5 inhibition in lymphoma. These studies have broad
implication to how RBPs can become dysregulated and their function controlled by PRMTs in B-cell lymphoma.
项目摘要/摘要
非霍奇金淋巴瘤(NHL)是最常见的癌症之一,尽管目前的治疗,许多
病人病情复发。最近的发现涉及表观遗传机制和非-
B细胞淋巴瘤患者中典型的致癌程序失调。蛋白质精氨酸
甲基转移酶-5(PRMT 5),负责精氨酸对称二甲基化的主要酶,
组蛋白和非组蛋白在淋巴瘤发生中起着重要作用,控制着
转化的B细胞。PRMT 5在淋巴瘤中过表达,可能代表了一种新的治疗靶点,
这种疾病。为了评估是什么调控因子驱动抗性,我们进行了全基因组CRISPR筛选。
令人惊讶的是,我们发现RNA结合蛋白MUSASHI 2(MSI 2)是最受欢迎的。MSI 2是一种RNA结合蛋白
在大多数植物中表达最高的茎相关蛋白质
侵袭性癌症,但其在B细胞淋巴瘤中的作用尚不清楚。我们的初步数据表明,MSI 2是
PRMT 5在淋巴瘤中高度表达,并且减少减少增殖,其通过PRMT 5抑制进一步减少。
我们还在B细胞淋巴瘤中发现了由PRMT 1和PRMT 5介导的新的翻译后修饰
并证明了这些新发现的修改的功能要求。我们建议研究这个问题
使用遗传小鼠模型、人淋巴瘤细胞系驱动淋巴瘤发生的新PRMT-MSI 2轴
和患者样本。此外,我们利用技术创新来研究直接MSI 2目标,
MSI 2如何介导对淋巴瘤中PRMT 5抑制的抗性的机制。这些研究具有广泛的
这意味着B细胞淋巴瘤中RBP如何变得失调以及其功能如何受到PRMT的控制。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Michael Kharas其他文献
Michael Kharas的其他文献
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{{ truncateString('Michael Kharas', 18)}}的其他基金
Identification of therapeutic targets for leukemia stem cells in AML-iPSC models
AML-iPSC 模型中白血病干细胞治疗靶点的鉴定
- 批准号:
10348154 - 财政年份:2018
- 资助金额:
$ 71.39万 - 项目类别:
Molecular and genetic analysis of novel Slicer-dependent miRNA pathways in blood
血液中新型 Slicer 依赖性 miRNA 通路的分子和遗传分析
- 批准号:
9219500 - 财政年份:2017
- 资助金额:
$ 71.39万 - 项目类别:
Uncovering the role for MSI2 network in hematopoietic stem cells
揭示 MSI2 网络在造血干细胞中的作用
- 批准号:
10265561 - 财政年份:2014
- 资助金额:
$ 71.39万 - 项目类别:
Uncovering the role for Msi2 in hematopoietic stem cells
揭示 Msi2 在造血干细胞中的作用
- 批准号:
9525948 - 财政年份:2014
- 资助金额:
$ 71.39万 - 项目类别:
Uncovering the role for MSI2 network in hematopoietic stem cells
揭示 MSI2 网络在造血干细胞中的作用
- 批准号:
10661727 - 财政年份:2014
- 资助金额:
$ 71.39万 - 项目类别:
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