TET2-mediated epitranscriptomic regulation in leukemia microenvironment
TET2介导的白血病微环境中的表观转录组调控
基本信息
- 批准号:10801348
- 负责人:
- 金额:$ 68.42万
- 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:2023-09-21 至 2028-08-31
- 项目状态:未结题
- 来源:
- 关键词:Acute Myelocytic LeukemiaApicalBasic ScienceBindingBiologicalBiological AssayBiological ProcessBiologyBone MarrowBone Marrow TransplantationCXCR4 geneCellsChemicalsChemoresistanceClonal ExpansionCoupledCytosineDNADNA binding protein BDNMT3aDataDevelopmentDioxygenasesDrug resistanceEnzymesFLT3 geneGenetic TranscriptionHematopoietic NeoplasmsHomingIn VitroInvestigationKnock-in MouseKnockout MiceKnowledgeLigandsMLL-AF9MLL-rearranged leukemiaMaintenanceMass Spectrum AnalysisMediatingMedicalMessenger RNAMethylationModelingModificationMolecularMusMutateMutationNPM1 geneNucleotidesPathway interactionsPatient-Focused OutcomesPatientsPlayPrognosisRNARNA StabilityRNA-Binding ProteinsRUNX1 geneRegimenRegulationRelapseReportingResolutionRoleSignal TransductionStromal Cell-Derived Factor 1Survival RateTestingTherapeuticTranscriptTransfer RNATransgenic OrganismsTreatment EfficacyValidationadverse outcomebisulfite sequencingchemokine receptorclinical prognosisconventional therapycrosslinking and immunoprecipitation sequencingdemethylationepitranscriptomicsgain of functionhematopoietic stem cell self-renewalhigh riskimprovedin vivoinfancyinhibitorleukemialeukemogenesisloss of functionmigrationmouse modelmutantnew therapeutic targetnoveloverexpressionoxidationpatient derived xenograft modelpharmacologicprogramsself-renewalstemtranscriptometranscriptome sequencingtranslational medicinetumor microenvironment
项目摘要
PROJECT SUMMARY: Background: Acute myeloid leukemia (AML) is one of the most aggressive types of
hematopoietic malignancies with various genetic alterations. Ten-Eleven Translocation 2 (TET2), an enzyme
involved in DNA demethylation, is deleted or mutated in 15-20% of AML patients. Those patients with TET2
deficiency are poorly responsive to currently available therapeutic regimens, leading to more adverse outcomes
than patients with other AML subtypes. Thus, it is urgent to identify new therapeutic target(s) and develop novel
effective approaches to treat TET2-deficient AMLs. Tet2 loss in mice facilitates the self-renewal of hematopoietic
stem cells (HSCs) and leukemic stem/initiating cells (LSCs/LICs). The LSCs/LICs reside in a specialized
microenvironment called “niche” in the bone marrow (BM) to support their survival and self-renewal. There are
several critical gaps in our current knowledge of the molecular mechanism underlying LSC/LIC homing
and of the role of TET2 deficiency in the BM microenvironment. Meanwhile, evidence is emerging to support
a novel function for TET2-mediated oxidation of methyl-5-cytosine (m5C) in RNAs, including messenger RNA
(mRNA). However, it is unknown whether and (if so) how TET2-mediated RNA m5C demethylation contributes
to leukemogenesis. Our preliminary study showed that Tet2 deficiency stimulates the Tetraspanin 13
(Tspan13)/C-X-C motif chemokine receptor 4 (Cxcr4) axis to facilitate AML homing/migration into the BM
microenvironment, giving rise to increased LSC/LIC self-renewal and fast leukemogenesis in vivo. Tet2
deficiency-mediated increase of mRNA m5C modification in Tspan13 is recognized by Y-box binding protein 1
(YBX1), which in turn stabilizes Tspan13 transcript and increases its expression, thereby activating the Cxcr4
signaling. Pharmacological inhibition of CXCR4 suppresses LSC/LIC homing into the BM microenvironment and
shows a synergistic effect with hypomethylating agents in killing TET2-deficient AMLs. These results lead to our
central hypothesis that TET2-mediated mRNA m5C demethylation is involved in reprogramming BM
microenvironment. Guided by strong preliminary data, we propose three Specific Aims to test our hypothesis: (1)
Determine the definitive role of TET2 in the homing of LSCs/LICs into BM microenvironment; (2) Characterize
the mRNA m5C-dependent and functionally essential targets of TET2 and decipher the molecular mechanisms
underlying the role of TET2 in LSC/LIC homing and self-renewal; and (3) Assess the therapeutic potential of
targeting the TET2/CXCR4 axis in high-risk TET2-deficient AMLs. Overall, our proposed studies will substantially
advance our understanding of the fundamental biology of TET2-mediated epitranscriptomic changes in BM
microenvironment and may result in the development of novel effective approaches to treat AMLs with TET2
deficiency. Thus, our project is of high novelty and significance in both basic research and translational medicine.
项目摘要:背景:急性髓系白血病(AML)是最具侵袭性的类型之一
具有各种基因改变的恶性血液病。10-11易位2(TET2),酶
在15%-20%的AML患者中,参与DNA去甲基化的基因缺失或突变。那些患有TET2的患者
缺乏对目前可用的治疗方案反应不佳,导致更多的不良后果
与其他AML亚型的患者相比,差异有统计学意义。因此,迫切需要寻找新的治疗靶点(S),开发新的治疗药物
治疗TET2缺乏的急性淋巴细胞白血病的有效方法。小鼠TET2缺失促进造血细胞自我更新
干细胞(HSCs)和白血病干细胞/起始细胞(LSCs/LICs)。LSC/LIC驻留在专门的
微环境在骨髓(BM)中被称为“小生境”,支持它们的生存和自我更新。确实有
我们目前对LSC/LIC归巢的分子机制了解中的几个关键差距
以及TET2缺乏在骨髓微环境中的作用。与此同时,越来越多的证据支持这一观点
TET2介导的包括信使RNA在内的RNA中甲基-5-胞嘧啶(M5C)氧化的新功能
(M RNA)。然而,目前尚不清楚TET2介导的RNA M5C去甲基化是否以及(如果是)是如何起作用的
与白血病的发生有关。我们的初步研究表明,TET2缺乏刺激了Tetraspan13
(Tspan13)/C-X-C基序趋化因子受体4(CXCR4)轴促进AML归巢/向骨髓迁移
微环境,导致体内LSC/LIC自我更新增加和快速白血病发生。TET2
Y-box结合蛋白1识别缺陷介导的Tspan13基因M5C修饰增加
(YBX1),进而稳定Tspan13转录本并增加其表达,从而激活CXCR4
发信号。CXCR4的药理抑制抑制LSC/LIC归巢到骨髓微环境和
显示出与低甲基化药物在杀死TET2缺乏的AML方面的协同效应。这些结果导致了我们的
TET2介导的M5C去甲基化参与骨髓重编程的中心假说
微环境。在强劲的初步数据的指导下,我们提出了三个具体目标来检验我们的假设:(1)
确定TET2在LSCs/LIC归巢到BM微环境中的决定性作用;(2)表征
TET2的M5C依赖和功能必需靶点及其分子机制的研究
TET2在LSC/LIC归巢和自我更新中的作用;以及(3)评估LSC/LIC的治疗潜力
在高危TET2缺陷的AML中靶向TET2/CXCR4轴。总括而言,我们建议的研究将大大
加深对TET2介导的骨髓表型转录改变的基础生物学的理解
微环境,并可能导致开发新的有效方法来治疗急性髓系白血病与TET2
缺乏症。因此,我们的项目在基础研究和转化医学方面都具有很高的新颖性和意义。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Jianjun Chen其他文献
Jianjun Chen的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Jianjun Chen', 18)}}的其他基金
The role and therapeutic potential of IGF2BP2 in MLL-rearranged leukemia
IGF2BP2 在 MLL 重排白血病中的作用和治疗潜力
- 批准号:
10579300 - 财政年份:2022
- 资助金额:
$ 68.42万 - 项目类别:
The role and therapeutic potential of IGF2BP2 in MLL-rearranged leukemia
IGF2BP2 在 MLL 重排白血病中的作用和治疗潜力
- 批准号:
10464855 - 财政年份:2022
- 资助金额:
$ 68.42万 - 项目类别:
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
- 批准号:
10549295 - 财政年份:2020
- 资助金额:
$ 68.42万 - 项目类别:
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
- 批准号:
10304942 - 财政年份:2020
- 资助金额:
$ 68.42万 - 项目类别:
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
- 批准号:
9914855 - 财政年份:2020
- 资助金额:
$ 68.42万 - 项目类别:
The role and mechanism of METTL3/METTL14-mediated RNA modification in the pathogenesis and drug-resistance of AML
METTL3/METTL14介导的RNA修饰在AML发病及耐药中的作用及机制
- 批准号:
10329928 - 财政年份:2019
- 资助金额:
$ 68.42万 - 项目类别:
Targeting FTO to treat acute myeloid leukemia
靶向FTO治疗急性髓系白血病
- 批准号:
10058254 - 财政年份:2019
- 资助金额:
$ 68.42万 - 项目类别:
Targeting FTO to treat acute myeloid leukemia
靶向FTO治疗急性髓系白血病
- 批准号:
10531853 - 财政年份:2019
- 资助金额:
$ 68.42万 - 项目类别:
The role and mechanism of METTL3/METTL14-mediated RNA modification in the pathogenesis and drug-resistance of AML
METTL3/METTL14介导的RNA修饰在AML发病及耐药中的作用及机制
- 批准号:
9765111 - 财政年份:2019
- 资助金额:
$ 68.42万 - 项目类别:
The role and mechanism of METTL3/METTL14-mediated RNA modification in the pathogenesis and drug-resistance of AML
METTL3/METTL14介导的RNA修饰在AML发病及耐药中的作用及机制
- 批准号:
10558640 - 财政年份:2019
- 资助金额:
$ 68.42万 - 项目类别:
相似国自然基金
FGF8通过Ras/MEK/ERK信号通路调控apical ES结构影响精子生成的机制研究
- 批准号:81801519
- 批准年份:2018
- 资助金额:21.0 万元
- 项目类别:青年科学基金项目
相似海外基金
Changes in apical cochlear mechanics after cochlear implantation
人工耳蜗植入后耳蜗顶端力学的变化
- 批准号:
10730981 - 财政年份:2023
- 资助金额:
$ 68.42万 - 项目类别:
Structural diversity of ceramide moiety responsible for apical membrane function of bladder transitional epithelial cells
负责膀胱移行上皮细胞顶膜功能的神经酰胺部分的结构多样性
- 批准号:
23K08792 - 财政年份:2023
- 资助金额:
$ 68.42万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Establishment of photodynamic diagnosis for apical periodontitis based on 5-ALA fluorescence live imaging
基于5-ALA荧光实时成像的根尖周炎光动力诊断方法的建立
- 批准号:
23K09188 - 财政年份:2023
- 资助金额:
$ 68.42万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Epithelial apical membrane polarization, morphogenesis, and regulation of gene expression
上皮顶膜极化、形态发生和基因表达调控
- 批准号:
BB/X000575/1 - 财政年份:2023
- 资助金额:
$ 68.42万 - 项目类别:
Research Grant
Unveiling Functional Roles of Apical Surface Interactions Between Opposing Cell Layers
揭示相对细胞层之间顶端表面相互作用的功能作用
- 批准号:
10629101 - 财政年份:2023
- 资助金额:
$ 68.42万 - 项目类别:
Evaluation of Trigeminal Ganglia Sensory Neuronal Population/s Mediating MIF-Induced Anti-Nociception in a Model of Apical Periodontitis.
根尖周炎模型中三叉神经节感觉神经元群介导 MIF 诱导的抗伤害感受的评估。
- 批准号:
10822712 - 财政年份:2023
- 资助金额:
$ 68.42万 - 项目类别:
Cell-type specific assembly of apical extracellular matrices
顶端细胞外基质的细胞类型特异性组装
- 批准号:
10749768 - 财政年份:2023
- 资助金额:
$ 68.42万 - 项目类别:
Exploring the role of phosphoinositides in the trafficking of proteins to the apical complex in the malaria parasite Plasmodium falciparum.
探索磷酸肌醇在疟原虫恶性疟原虫顶复合体蛋白质运输中的作用。
- 批准号:
495093 - 财政年份:2023
- 资助金额:
$ 68.42万 - 项目类别:
Operating Grants
Étude du rôle de la phosphatase de phosphoinositides SAC1 dans le trafic de protéines au complexe apical chez le parasite de la malaria Plasmodium falciparum
疟疾疟原虫顶端寄生虫复合物中磷酸肌醇磷酸酶 SAC1 的研究
- 批准号:
486094 - 财政年份:2022
- 资助金额:
$ 68.42万 - 项目类别:
Studentship Programs
Illuminating apical extracellular matrix structure and biogenesis
阐明顶端细胞外基质结构和生物发生
- 批准号:
10654029 - 财政年份:2022
- 资助金额:
$ 68.42万 - 项目类别: