Impact of RPS15 mutation on development and progression of chronic lymphocytic leukemia
RPS15突变对慢性淋巴细胞白血病发生发展的影响
基本信息
- 批准号:9921200
- 负责人:
- 金额:$ 3.7万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-07-01 至 2023-06-30
- 项目状态:已结题
- 来源:
- 关键词:ATR geneAdultAffectAnabolismAutomobile DrivingB-LymphocytesBiological AssayBiologyCD19 geneCRISPR/Cas technologyCell LineCell physiologyCellsChronic Lymphocytic LeukemiaClinicalComplexDNA Sequence AlterationDevelopmentDiamond-Blackfan anemiaDiseaseDrug resistanceEventExonsExpression ProfilingFrequenciesFutureGene ExpressionGene Expression RegulationGene MutationGene ProteinsGenesGeneticGenetic TranslationGrowth FactorHomeostasisHumanImmuno-ChemotherapyIn VitroInitiator CodonKnock-in MouseLesionMDM2 geneMalignant - descriptorMalignant NeoplasmsMessenger RNAMissense MutationModelingMusMutateMutationNorthern BlottingOncogenesOutcomePaintParticipantPathogenesisPathologyPathway interactionsPatientsPhenotypePhysiologicalPlayProteinsProteomeProtocols documentationRNA chemical synthesisRecurrenceRefractoryRegulationRegulator GenesRelapseReportingRibosomal ProteinsRibosomal RNARibosomesRoleSiteStressSyndromeTP53 geneTechniquesTechnologyTerminator CodonTherapeutic InterventionTissuesTranscriptTranslationsTumorigenicitycell growth regulationchromosome 13q losschromosome 17p losschronic lymphocytic leukemia cellcohorteffective therapyexome sequencingexperimental studyin vivoinsightlentiviral integrationleukemialeukemogenesisloss of function mutationmouse modelmutantnext generation sequencingnoveloutcome forecastpatient populationprotein functionrelapse riskribosome profilingtargeted treatmenttherapy resistanttooltumortumor progressiontumorigenic
项目摘要
Project Summary/Abstract
There is mounting evidence that ribosomes are more dynamic and heterogenous than previously described.
Advances in our understanding of ribosomal functions now paint a picture of ribosomes as critical regulators of
gene expression with unique compositions and highly specialized functions that can differ across tissue types.
Aberrant ribosome activity has been assessed in many tumor types and recurrent mutations in ribosomal proteins
have been reported in a number of cancers and ribosomopathies associated with cancer, such as T-ALL and
Diamond-Blackfan anemia. This can include changes in the fidelity and rate of translation, preferential translation
of certain transcripts over others, utilization of alternative start and stop codons, and overall changes in intra-
cellular ribosome content. Recent whole exome sequencing studies of 538 patients with chronic lymphocytic
leukemia (CLL) have identified recurrent missense mutations (~5%) at a hotspot region of ribosomal protein S15
(RPS15). RPS15 mutations often co-occur with TP53 aberrations (36%) and are enriched in del(17p) CLL (12%)
– abnormalities that are often carry poor prognoses and refractoriness to chemoimmunotherapy. Indeed,
mutation of RPS15 is associated with adverse prognosis and an increased risk of relapse following chemo-
immunotherapy, even in the absence of TP53 or del(17p) deletions. However, despite these compelling clinical
findings, there is a paucity of information regarding how RPS15 mutation influences CLL pathogenesis. We have
generated an array of unique tools for the proposed study of this essential protein that promise to unravel this
mechanism. This includes human CLL cell lines that are well characterized and carry genetic mutations that
reflect common CLL lesions, such as del(13q) and TP53, and that have been edited to express RPS15 mutations
relevant in CLL. We have also generated physiologically faithful Rps15 knock-in mice that restrict mutant
expression to B cells. Using these models to characterize the functional impact of this mutation on CLL
development and progression will certainly provide new directions for therapeutic intervention and will add to our
fundamental understanding of ribosome pathology. The proposed study seeks to thoroughly interrogate the
impact of RPS15 mutations on CLL biology through the following aims: 1) Characterize its influence on ribosomal
protein functions (such as ribosomal RNA synthesis, ribosome assembly, translation and extra-ribosomal
functions – namely, the MDM2-P53 ribosome surveillance pathway) in both healthy and malignant tissue; and
2) Determine its impact on cancer hallmarks such as proliferation and growth factor independence in vitro and
on tumorigenicity in vivo. Because RPS15 mutations engage the mRNA decoding site, we hypothesize that they
contribute to pathogenesis through aberrant translation of mRNA. The proposed experimental approaches
include complex and novel techniques such as ribosome characterization, ribosome profiling, FISH, ribosomal
RNA characterization through northern blotting, and tumorigenicity studies using in vitro and in vivo CLL models.
项目概要/摘要
越来越多的证据表明核糖体比之前描述的更具动态性和异质性。
我们对核糖体功能理解的进步现在描绘了核糖体作为关键调节剂的画面
具有独特组成和高度专业化功能的基因表达在不同组织类型中可能有所不同。
已在许多肿瘤类型和核糖体蛋白的反复突变中评估了异常核糖体活性
已报道多种癌症和与癌症相关的核糖体病,例如 T-ALL 和
戴蒙德-布莱克范贫血。这可能包括翻译保真度和速度的变化、优先翻译
某些转录本相对于其他转录本的差异、替代起始密码子和终止密码子的利用以及内部的总体变化
细胞核糖体含量。最近对 538 名慢性淋巴细胞白血病患者进行的全外显子组测序研究
白血病 (CLL) 在核糖体蛋白 S15 的热点区域发现了复发性错义突变 (~5%)
(RPS15)。 RPS15 突变通常与 TP53 畸变同时发生 (36%),并且在 del(17p) CLL 中富集 (12%)
– 通常会带来不良预后和化学免疫治疗无效的异常。的确,
RPS15 突变与不良预后和化疗后复发风险增加相关
免疫疗法,即使没有 TP53 或 del(17p) 缺失。然而,尽管有这些引人注目的临床
研究结果表明,关于 RPS15 突变如何影响 CLL 发病机制的信息很少。我们有
为这种必需蛋白质的拟议研究生成了一系列独特的工具,有望解开这个谜团
机制。这包括经过充分表征并携带基因突变的人类 CLL 细胞系
反映常见的 CLL 病变,例如 del(13q) 和 TP53,并且已被编辑以表达 RPS15 突变
与 CLL 相关。我们还培育了生理上忠实的 Rps15 敲入小鼠,可限制突变
表达至 B 细胞。使用这些模型来表征该突变对 CLL 的功能影响
发展和进展必将为治疗干预提供新的方向,并将增加我们的研究成果。
对核糖体病理学的基本了解。拟议的研究旨在彻底询问
通过以下目标研究 RPS15 突变对 CLL 生物学的影响:1) 表征其对核糖体的影响
蛋白质功能(如核糖体RNA合成、核糖体组装、翻译和核糖体外合成)
健康和恶性组织中的功能(即 MDM2-P53 核糖体监视途径);和
2) 确定其对癌症标志的影响,例如体外增殖和生长因子独立性
体内致瘤性。由于 RPS15 突变涉及 mRNA 解码位点,我们假设它们
通过 mRNA 的异常翻译促进发病机制。提出的实验方法
包括复杂和新颖的技术,例如核糖体表征、核糖体分析、FISH、核糖体
通过 Northern blotting 进行 RNA 表征,并使用体外和体内 CLL 模型进行致瘤性研究。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
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Catherine Gutierrez其他文献
Catherine Gutierrez的其他文献
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{{ truncateString('Catherine Gutierrez', 18)}}的其他基金
Impact of RPS15 mutation on development and progression of chronic lymphocytic leukemia
RPS15突变对慢性淋巴细胞白血病发生发展的影响
- 批准号:
10170297 - 财政年份:2019
- 资助金额:
$ 3.7万 - 项目类别:
Impact of RPS15 mutation on development and progression of chronic lymphocytic leukemia
RPS15突变对慢性淋巴细胞白血病发生发展的影响
- 批准号:
9758073 - 财政年份:2019
- 资助金额:
$ 3.7万 - 项目类别:
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