Clinical and Genetic Origins of Monomorphic Epitheliotropic Intestinal T Cell Lymphoma
单形性上皮性肠 T 细胞淋巴瘤的临床和遗传起源
基本信息
- 批准号:10566317
- 负责人:
- 金额:$ 41.66万
- 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:2023-01-01 至 2027-12-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAffectBiologicalCeliac DiseaseCell Differentiation processCell physiologyCellsClinicalDNA DamageDNA RepairDevelopmentDiseaseDisease modelExhibitsExonsFrequenciesGene SilencingGenerationsGenesGeneticGenetic TranscriptionGenomicsHistone H3Intestinal NeoplasmsIntestinesKnock-outKnockout MiceKnowledgeLeadLymphocyteLymphomaLymphomagenesisLysineMalignant NeoplasmsMeasuresMessenger RNAMethylationModelingModificationMolecularMutateMutationOncogene ActivationOncogenesOutcomePathogenesisPathway interactionsPatientsPhenotypePopulationPremalignant CellProcessPrognosisRNA SplicingRag1 MouseRecording of previous eventsRoleSTAT5B geneSiteT-Cell DevelopmentT-Cell LymphomaT-LymphocyteT-cell receptor repertoireTechniquesTestingTherapeuticTreatment ProtocolsV(D)J RecombinationWorkcell transformationdesigneffective therapygenotoxicityhistone methyltransferaseimprovedinnovationintraepithelialmouse modelnovelnovel therapeutic interventionoverexpressionpremalignantrecruitresponsesingle-cell RNA sequencingstandard of caretumorγδ T cells
项目摘要
ABSTRACT
Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is a rare but lethal disease with a median
survival of 1 year. There is no current effective standard-of-care. Previous MEITL sequencing efforts performed
by our group and others have revealed SETD2 as one of the most frequently altered genes in this disease.
SETD2 directs trimethylation of the lysine 36 residue on histone H3 (H3K36me3), which in turn is associated
with active transcription of genes. SETD2 has been implicated in DNA damage repair and mRNA splicing.
However, the molecular role of SETD2 and its interaction with activated oncogenes in MEITL pathogenesis is
largely unknown.
In this proposal, we will utilize a conditional mouse model to determine how SETD2 loss contributes to the
creation of a premalignant pool of intestinal intraepithelial cells (IELs), the cell of origin of MEITL. We will also
investigate how the combination of SETD2 loss and activation of the oncogenes STAT5B or MYC lead to IEL
transformation. Finally, we will determine the extent to which SETD2 deficiency sensitizes T lymphoma cells to
a variety of genotoxic chemotherapeutics. We anticipate that the results of this work will have immediate impact
on the design of effective treatment regimens that target MEITL and other SETD2-deficient lymphomas.
摘要
单形性肠嗜上皮性T细胞淋巴瘤(MEITL)是一种罕见但致命的疾病,
生存1年。目前没有有效的标准治疗。先前进行的MEITL测序工作
我们小组和其他人已经揭示了SETD 2是这种疾病中最常见的改变基因之一。
SETD 2指导组蛋白H3上赖氨酸36残基的三甲基化(H3K36me3),其又与
基因的活跃转录。SETD 2与DNA损伤修复和mRNA剪接有关。
然而,SETD 2的分子作用及其与活化的癌基因在MEITL发病机制中的相互作用是未知的。
大部分未知。
在本提案中,我们将利用条件小鼠模型来确定SETD2丢失如何有助于
产生肠上皮内细胞(IEL)的癌前池,MEITL的起源细胞。我们还将
研究SETD2缺失和癌基因STAT5B或MYC激活的组合如何导致IEL
转型最后,我们将确定SETD 2缺陷在多大程度上使T淋巴瘤细胞对
各种基因毒性化疗药物。我们预期这项工作的结果将立即产生影响
设计针对MEITL和其他SETD 2缺陷型淋巴瘤的有效治疗方案。
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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Sandeep Dave其他文献
Sandeep Dave的其他文献
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{{ truncateString('Sandeep Dave', 18)}}的其他基金
Genetic Origins of Adverse Outcomes in African Americans with Lymphoma
非裔美国人淋巴瘤不良后果的遗传起源
- 批准号:
10587289 - 财政年份:2023
- 资助金额:
$ 41.66万 - 项目类别:
Defining the Functional Role of Mutations in Diffuse Large B cell Lymphoma
定义突变在弥漫性大 B 细胞淋巴瘤中的功能作用
- 批准号:
9040901 - 财政年份:2015
- 资助金额:
$ 41.66万 - 项目类别:
Exome-wide screening for common mutations in lymphoma
淋巴瘤常见突变的全外显子组筛查
- 批准号:
8190377 - 财政年份:2011
- 资助金额:
$ 41.66万 - 项目类别:
Exome-wide screening for common mutations in lymphoma
淋巴瘤常见突变的全外显子组筛查
- 批准号:
8279186 - 财政年份:2011
- 资助金额:
$ 41.66万 - 项目类别:
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