The function and underlying mechanism of TET1 in myelodysplastic syndromes
TET1在骨髓增生异常综合征中的功能及机制
基本信息
- 批准号:9914855
- 负责人:
- 金额:$ 56.49万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-03-10 至 2023-12-31
- 项目状态:已结题
- 来源:
- 关键词:Acute Myelocytic LeukemiaAddressAnemiaAnimal GeneticsAnimal ModelAttenuatedBasic ScienceBlood CellsBone Marrow TransplantationCell Differentiation processCellsChIP-seqChromosome abnormalityClonal Hematopoietic Stem CellControl GroupsDNADNA MethylationDataData SetDevelopmentDioxygenasesDiseaseDown-RegulationDysmyelopoietic SyndromesEZH2 geneEpigenetic ProcessFLT3 geneFamilyFutureGene Expression ProfilingGene MutationGenesGoalsHematopoiesisHematopoieticHematopoietic stem cellsHistonesHumanIn VitroKnock-outLeadLeukopeniaMLL geneMaintenanceMalignant - descriptorMalignant NeoplasmsModelingModificationMolecularMusMutateMutationMyelogenousMyeloproliferative diseaseNPM1 geneOncogenicPathogenesisPathologicPatientsPhenotypePlayProtein translocationReportingResearch DesignRiskRoleSamplingSignal PathwaySignal TransductionSolidThrombocytopeniaTranslational ResearchTransplant RecipientsTumor Suppressor GenesTumor Suppressor ProteinsValidationWorkXenograft procedurecohortcytopeniademethylationgain of functiongene translocationgenome-widegranulocyte-monocyte progenitorshematopoietic differentiationhigh riskin vivoinsightknock-downloss of functionloss of function mutationmembermutantnew therapeutic targetnoveloverexpressionperipheral bloodprogenitorsuccesst(821)(q22q22)transcriptome sequencingtransplant modelwhole genome
项目摘要
PROJECT SUMMARY (ABSTRACT):
Title: The function and underlying mechanism of TET1 in myelodysplastic syndromes.
Background: Myelodysplastic syndromes (MDS) is a heterogenous group of clonal hematopoietic stem cell
disorders, characterized by peripheral blood (PB) cytopenias (e.g., anemia, leukopenia, and thrombocytopenia).
Although chromosomal abnormalities, gene mutations and some histone/DNA epigenetic changes have been reported
in MDS, the molecular mechanisms underlying the pathogenesis of MDS have not been well understood. TET1, the
founding member of the TET methylcytosine dioxygenase family, was first identified as a fusion partner of the
MLL gene in acute myeloid leukemia (AML). In contrast to the previous thought that all three TET genes
(TET1/2/3) may function as tumor suppressor genes in cancers, our recent work showed that TET1 is
overexpressed in certain subtypes of AMLs, and plays a critical oncogenic role in the development of such AMLs.
However, the role of TET1 in MDS remains unknown. Recently, in analysis of a genome-wide gene expression
profiling dataset of a large cohort of human primary MDS patients, we found that TET1 is also aberrantly
overexpressed in all the major subtypes of MDS analyzed, which was confirmed by qPCR in our in-house MDS
samples. Tet1 is also overexpressed in various murine MDS models. We then showed that knockdown of TET1
expression substantially promoted differentiation of MDS cells, and forced expression of wild-type TET1 (but not
catalytic inactive TET1 mutant) caused the opposite phenomenon. TET1 depletion also significantly inhibited
MDS progression and diminished cytopenias in vivo. Furthermore, we have identified a set of potential/candidate
target genes of TET1 in MDS, and some of them have been implicated in the pathogenesis of MDS.
Objective/Hypothesis: TET1 plays an essential role in MDS pathogenesis through epigenetically regulating
expression of a set of essential target genes.
Specific Aims: (1) To determine whether TET1 is required for the development and maintenance of MDS;
(2) To determine whether forced expression of TET1 can promote MDS development and progression, and
whether TET1 function is dependent on its catalytic activity; and (3) To decipher the molecular mechanism(s)
underlying the pathological role of TET1 in MDS.
Study Design: 1) We will conduct loss-of-function studies in genetic animal MDS models and patient-derived
xeno-transplantation (PDX) MDS models to determine whether Tet1/TET1 expression/function is required for both
development and maintenance of MDS (Aim 1). 2) We will conduct gain-of-function studies with the above MDS
models to determine whether forced expression of Tet1/TET1 can promote MDS development and progression
via a catalytic activity-dependent mechanism (Aim 2). 3) We will perform genome-wide ChIP-seq, 5hmC-seq,
and RNA-seq to identify all direct targets of TET1 in MDS, followed by the validation/functional studies of a set
of top targets of TET1 in vitro and in vivo, to elucidate the molecular mechanism underlying TET1’s role (Aim 3).
项目概要(摘要):
标题:TET1 在骨髓增生异常综合征中的功能和潜在机制。
背景:骨髓增生异常综合征(MDS)是一组异质性克隆造血干细胞
以外周血 (PB) 血细胞减少为特征的疾病(例如贫血、白细胞减少和血小板减少)。
尽管染色体异常、基因突变和一些组蛋白/DNA 表观遗传变化已有报道
在 MDS 中,MDS 发病机制的分子机制尚未得到充分了解。
TET 甲基胞嘧啶双加氧酶家族的创始成员,首次被鉴定为
急性髓系白血病(AML)中的MLL基因与之前认为的所有三个TET基因相反。
(TET1/2/3)可能作为癌症中的抑癌基因,我们最近的工作表明TET1是
在 AML 的某些亚型中过度表达,并在此类 AML 的发展中发挥关键的致癌作用。
然而,最近在全基因组基因表达分析中,TET1 在 MDS 中的作用仍不清楚。
通过对一大群人类原发性 MDS 患者的分析数据集,我们发现 TET1 也存在异常
在所分析的所有主要 MDS 亚型中均过表达,这在我们内部 MDS 中通过 qPCR 得到了证实
Tet1 在各种小鼠 MDS 模型中也过度表达,然后我们证明了 TET1 的敲低。
MDS 细胞的表达显着分化,并强制表达野生型 TET1(但不
催化失活的 TET1 突变体)引起的相反现象也被显着抑制。
此外,我们还确定了一组潜在的/候选的药物。
TET1在MDS中的靶基因,其中一些与MDS的发病机制有关。
目的/假设:TET1 通过表观遗传调控在 MDS 发病机制中发挥重要作用
一组重要靶基因的表达。
具体目标: (1) 确定MDS的开发和维护是否需要TET1;
(2) 确定TET1的强制表达是否可以促进MDS的发生和进展,以及
TET1 的功能是否取决于其催化活性;以及 (3) 破译分子机制
TET1 在 MDS 中的病理作用的基础。
研究设计: 1)我们将在遗传动物MDS模型和患者来源的模型中进行功能丧失研究
异种移植 (PDX) MDS 模型以确定 Tet1/TET1 表达/功能是否是两者所必需的
MDS 的开发和维护(目标 2)我们将利用上述 MDS 进行功能获得研究。
确定 Tet1/TET1 的强制表达是否可以促进 MDS 发生和进展的模型
通过催化活性依赖机制(目标 3)我们将进行全基因组 ChIP-seq、5hmC-seq、
和 RNA-seq 来识别 MDS 中 TET1 的所有直接靶点,然后对一组进行验证/功能研究
体外和体内 TET1 的主要靶标,以阐明 TET1 作用的分子机制(目标 3)。
项目成果
期刊论文数量(0)
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Jianjun Chen其他文献
Jianjun Chen的其他文献
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{{ truncateString('Jianjun Chen', 18)}}的其他基金
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- 资助金额:
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The role and therapeutic potential of IGF2BP2 in MLL-rearranged leukemia
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- 批准号:
10464855 - 财政年份:2022
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The role and therapeutic potential of IGF2BP2 in MLL-rearranged leukemia
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10579300 - 财政年份:2022
- 资助金额:
$ 56.49万 - 项目类别:
The function and underlying mechanism of TET1 in myelodysplastic syndromes
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10549295 - 财政年份:2020
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The function and underlying mechanism of TET1 in myelodysplastic syndromes
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