Cooperative role of TET2 and IDH2 mutations in angioimmunoblastic T-cell lymphomagenesis
TET2 和 IDH2 突变在血管免疫母细胞 T 细胞淋巴瘤发生中的协同作用
基本信息
- 批准号:10299140
- 负责人:
- 金额:$ 50.08万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-08-01 至 2026-07-31
- 项目状态:未结题
- 来源:
- 关键词:AffectAggressive Clinical CourseArginineB-LymphocytesCD28 geneCD4 Positive T LymphocytesCRISPR/Cas technologyCell Differentiation processCell LineCell modelCellsCharacteristicsClinicalClonal ExpansionDNADNA MethylationDevelopmentDiagnosisDiseaseEnzymesEpigenetic ProcessEventFamily memberGene ExpressionGene Expression ProfilingGene MutationGenesGeneticGenomicsGlutamineGoalsHelper-Inducer T-LymphocyteHematologic NeoplasmsHematopoiesisHematopoietic stem cellsHumanImmunoblastic LymphadenopathyImmunophenotypingIn VitroInduced MutationKnockout MiceLeadLesionLymphomaLymphomagenesisMalignant - descriptorMalignant lymphoid neoplasmMediatingMetabolicModificationMolecularMusMutationMyeloid CellsMyeloproliferative diseaseOncogenicOutcomePathogenesisPathogenicityPathologicPathway interactionsPatientsPeripheralPhenotypePlayPre-Clinical ModelPreclinical TestingProductionPrognosisRHOA geneResearchRoleSamplingSpecimenStromal CellsSystemT cell differentiationT-Cell ActivationT-Cell DevelopmentT-Cell LymphomaT-Cell TransformationT-LymphocyteTestingTherapeutic InterventionTransgenic OrganismsValidationaccurate diagnosiscell transformationdrug efficacyeffective therapyefficacy studyefficacy testingepigenomeepigenomicsgenome-widehistone demethylasehuman modelinhibitor/antagonistinsightloss of function mutationmouse modelmutantmutant mouse modelneoplasticneoplastic cellnovelnovel therapeutic interventionnovel therapeuticspatient derived xenograft modelpolarized cellpre-clinicalprogramstargeted treatmenttherapeutic evaluationtreatment responsetumortumor microenvironment
项目摘要
Abstract
Angioimmunoblastic T-cell lymphoma (AITL) is the most common subtype of peripheral T-cell lymphoma
(PTCL) with distinct pathological and clinical characteristics. It is a difficult-to-diagnose and lacks effective
therapies due to poor understanding of the molecular pathogenesis. Using genome-wide gene expression
profiling (GEP), we have defined a robust molecular classifier for accurate diagnosis, identified oncogenic
pathways, discovered its cell-of-origin, and deciphered the role of the tumor milieu in disease prognosis. Using
high-throughput genomic analysis, we also identified frequent mutations in epigenetic regulators (TET2, IDH2
and DNMT3A) and regulators of T-cell activation (RHOA and CD28) in AITL. Co-occurrence of TET2 mutations
with IDH2 mutation (hotspot: arginine-172; IDH2R172) is unique in AITL compared to other hematological
malignancies where they are mutually exclusive, suggesting their cooperative role in T-cell lymphomagenesis.
We have generated unique murine models with conditional loss of Tet2 (Tet2-/-) and double mutant (Tet2-/-
/IDH2R172K) in CD4+ T-cells, and murine lymphomas with follicular helper T-cell (TFH) phenotype were observed.
In addition, we generated several patient-derived xenografts (PDX) of AITL with IDH2R172 and/or TET2 mutations.
We hypothesize that TET2 deficiency in T cells alters the DNA methylation profile leading to an altered
genetic program favoring TFH cell differentiation and clonal expansion, facilitating transformation with
subsequent hits, including IDH2R172 mutation, which will further alter the epigenome and oncogenic
pathways in TFH -cell transformation. We will define the precise role of these genetic lesions in T-cell
differentiation and in AITL pathogenesis. We also edited normal human CD4+ T-cells using CRISPR/CAS9 to
generate TET2-/- T-cells for functional analysis and cross-validation of murine models. SinceTET2 mutations are in
hematopoietic stem/progenitor cells (HSPC) in some AITLs, interactions between TET2 deficient T- and stromal
cells during lymphomagenesis will be explored. We will test the efficacy of therapeutic interventions, including
demethylating agents for TET2 deficiency and IDH2 inhibitors and/or glutamine depletion for TET2/IDH2 double
mutant tumors in murine models and PDX of AITL. To accomplish the objective, three aims are planned:
Specific Aim 1: To determine the mechanisms by which Tet2 deficiency mediates T-cell transformation and the
role of Tet2 mutation in stromal cells in lymphomagenesis.
Specific Aim 2: To delineate the mechanisms of combined Tet2 and IDH2R172K mutations in AITL pathogenesis.
Specific Aim 3: To evaluate therapies targeting oncogenic mechanisms mediated by Tet2 and IDH2R172
mutations.
Our long-term research goal is to define the pathobiology of AITL, through integrated functional epigenomic
approaches using in vitro modified human T-cells, patient samples and relevant murine models, thus identifying
promising novel targets for treatment that may be tested pre-clinically in PDX models.
摘要
血管免疫母细胞T细胞淋巴瘤(AITL)是外周T细胞淋巴瘤最常见的亚型
(PTCL)具有明显的病理和临床特征。本病诊断困难,疗效欠佳。
由于对其分子发病机制认识不清,导致治疗效果不佳。使用全基因组的基因表达
简档分析(GEP),我们定义了一个强大的分子分类器,用于准确诊断、鉴定致癌因素
途径,发现其起源的细胞,并破译了肿瘤环境在疾病预后中的作用。vbl.使用
高通量基因组分析,我们还发现了表观遗传调控因子(TET2,IDH2)的频繁突变
和DNMT3A)以及AITL中T细胞激活的调节因子(RHOA和CD28)。TET2突变的并存
IDH2突变(热点:精氨酸-172;IDH2 R172)与其他血液病相比在AITL中是独一无二的
它们相互排斥的恶性肿瘤,表明它们在T细胞淋巴肿大中的协同作用。
我们已经建立了具有条件缺失TET2(TET2-/-)和双突变(TET2-/-)的独特的小鼠模型
/IDH2 R172K)的表达,以及滤泡辅助性T细胞(TFH)表型的小鼠淋巴瘤。
此外,我们产生了几个带有IDH2 R172和/或TET2突变的AITL患者来源的异种移植(PDX)。
我们假设T细胞中缺乏TET2会改变DNA甲基化特征,从而导致改变
有利于TFH细胞分化和克隆性扩增的遗传程序,促进了
后续的HITS,包括IDH2 R172突变,这将进一步改变表观基因组和致癌基因
TFH-细胞转化途径。我们将确定这些遗传损伤在T细胞中的确切作用
在AITL的发病机制中起重要作用。我们还使用CRISPR/Cas9编辑了正常人的CD4+T细胞,以
为小鼠模型的功能分析和交叉验证生成TET2-/-T细胞。因为TET2突变是在
某些AITL中的造血干/祖细胞(HSPC)、TET2缺陷T细胞与基质的相互作用
本课程将探讨淋巴瘤发生过程中的细胞。我们将测试治疗干预的效果,包括
TET2缺乏症的去甲基化药物和IDH2抑制剂和/或TET2/IDH2双链的谷氨酰胺耗竭
AITL小鼠模型中的突变肿瘤和PDX。为实现这一目标,计划实现三个目标:
具体目标1:确定TET2缺乏介导T细胞转化的机制
间质细胞TET2突变在淋巴瘤发生中的作用
目的2:探讨TET2和IDH2 R172K联合突变在AITL发病机制中的作用。
具体目标3:评估针对TET2和IDH2 R172介导的致癌机制的治疗
突变。
我们的长期研究目标是通过整合的功能表观基因组来确定AITL的病理生物学
使用体外修饰的人T细胞、患者样本和相关小鼠模型的方法,从而识别
有望在PDX模型中进行临床前测试的治疗新靶点。
项目成果
期刊论文数量(0)
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会议论文数量(0)
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Wing C. Chan其他文献
Heterogeneity of large granular lymphocyte proliferations: delineation of two major subtypes.
大颗粒淋巴细胞增殖的异质性:两种主要亚型的划分。
- DOI:
- 发表时间:
1986 - 期刊:
- 影响因子:20.3
- 作者:
Wing C. Chan;A. Mawle;Irene J. Check;Russell K. Brynes;Elliott F. Winton - 通讯作者:
Elliott F. Winton
Mechanistic Elucidation of the Tumor-Promoting Role of Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1 in B-Cell Receptor Signaling in Mantle Cell Lymphoma
- DOI:
10.1182/blood-2023-175064 - 发表时间:
2023-11-02 - 期刊:
- 影响因子:
- 作者:
Serene Xavier;Vivian Nguyen;Vishal Khairnar;An Phan;Lu Yang;Michael Nelson;Elizabeth Tseng;Aimin Li;Joo Y Song;Dennis D. Weisenburger;Wing C. Chan;Markus Müschen;Vu N. Ngo - 通讯作者:
Vu N. Ngo
Lymphomas of follicles. Mantle cell and follicle center cell lymphomas.
滤泡淋巴瘤。
- DOI:
- 发表时间:
1993 - 期刊:
- 影响因子:3.5
- 作者:
D. Weisenburger;Wing C. Chan - 通讯作者:
Wing C. Chan
Large granular lymphocyte proliferation: an analysis of T-cell receptor gene arrangement and expression and the effect of in vitro culture with inducing agents.
大颗粒淋巴细胞增殖:T细胞受体基因排列和表达以及诱导剂体外培养效果的分析。
- DOI:
- 发表时间:
1988 - 期刊:
- 影响因子:20.3
- 作者:
Wing C. Chan;Carol DahI;Thomas A. Waldmann;Susan Link;Alison Mawle;Janet K. A. Nicholson;Fritz H. Bach;K. Bongiovanni;Peter A. McCue;Elliott F. Winton - 通讯作者:
Elliott F. Winton
Peripheral T cell lymphomas: from the bench to the clinic
外周 T 细胞淋巴瘤:从实验室到临床
- DOI:
10.1038/s41568-020-0247-0 - 发表时间:
2020-04-06 - 期刊:
- 影响因子:66.800
- 作者:
Danilo Fiore;Luca Vincenzo Cappelli;Alessandro Broccoli;Pier Luigi Zinzani;Wing C. Chan;Giorgio Inghirami - 通讯作者:
Giorgio Inghirami
Wing C. Chan的其他文献
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{{ truncateString('Wing C. Chan', 18)}}的其他基金
Pre-analytical variables of bioanalytes affecting the accuracy of PTCL diagnostic and prognostic genetic signatures
生物分析物的分析前变量影响 PTCL 诊断和预后遗传特征的准确性
- 批准号:
10300391 - 财政年份:2021
- 资助金额:
$ 50.08万 - 项目类别:
Pre-analytical variables of bioanalytes affecting the accuracy of PTCL diagnostic and prognostic genetic signatures
生物分析物的分析前变量影响 PTCL 诊断和预后遗传特征的准确性
- 批准号:
10491082 - 财政年份:2021
- 资助金额:
$ 50.08万 - 项目类别:
Cooperative role of TET2 and IDH2 mutations in angioimmunoblastic T-cell lymphomagenesis
TET2 和 IDH2 突变在血管免疫母细胞 T 细胞淋巴瘤发生中的协同作用
- 批准号:
10672370 - 财政年份:2021
- 资助金额:
$ 50.08万 - 项目类别:
Pre-analytical variables of bioanalytes affecting the accuracy of PTCL diagnostic and prognostic genetic signatures
生物分析物的分析前变量影响 PTCL 诊断和预后遗传特征的准确性
- 批准号:
10684317 - 财政年份:2021
- 资助金额:
$ 50.08万 - 项目类别:
Cooperative role of TET2 and IDH2 mutations in angioimmunoblastic T-cell lymphomagenesis
TET2 和 IDH2 突变在血管免疫母细胞 T 细胞淋巴瘤发生中的协同作用
- 批准号:
10453656 - 财政年份:2021
- 资助金额:
$ 50.08万 - 项目类别:
Development of a Novel Clinical Diagnostic Assay for Peripheral T-cell Lymphoma (PTCL)
开发外周 T 细胞淋巴瘤 (PTCL) 的新型临床诊断方法
- 批准号:
9555564 - 财政年份:2018
- 资助金额:
$ 50.08万 - 项目类别:
Molecular diagnostic and prognostic signatures for PTCL
PTCL 的分子诊断和预后特征
- 批准号:
10017897 - 财政年份:2017
- 资助金额:
$ 50.08万 - 项目类别:
Molecular diagnostic and prognostic signatures for PTCL
PTCL 的分子诊断和预后特征
- 批准号:
10226182 - 财政年份:2017
- 资助金额:
$ 50.08万 - 项目类别:
Molecular Signatures to Improve Diagnosis and Outcome Pr
改善诊断和结果的分子特征
- 批准号:
7913564 - 财政年份:2009
- 资助金额:
$ 50.08万 - 项目类别:
Gene expression profiling and pathway targeted therapy in peripheral T-cell
外周T细胞的基因表达谱和通路靶向治疗
- 批准号:
7715220 - 财政年份:2009
- 资助金额:
$ 50.08万 - 项目类别: