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:
    10453656
  • 负责人:
  • 金额:
    $ 47.86万
  • 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

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 血管免疫母细胞性T细胞淋巴瘤(AITL)是外周T细胞淋巴瘤中最常见的亚型 PTCL具有独特的病理和临床特征。该病诊断困难,缺乏有效的 由于对分子发病机制的理解不足,利用全基因组基因表达 基因表达谱(GEP),我们已经定义了一个强大的分子分类器,用于准确诊断,识别致癌基因 研究人员发现了它的起源细胞,并破译了肿瘤环境在疾病预后中的作用。使用 通过高通量基因组分析,我们还鉴定了表观遗传调节因子(TET 2,IDH 2)中的频繁突变 和DNMT 3A)和T细胞活化的调节剂(RHOA和CD 28)。TET 2突变的共现 IDH 2突变(热点:精氨酸-172; IDH 2 R172)在AITL中是独特的,与其他血液学 恶性肿瘤,它们是相互排斥的,这表明它们在T细胞淋巴瘤发生中的合作作用。 我们已经产生了具有Tet 2条件性缺失(Tet 2-/-)和双突变体(Tet 2-/-)的独特小鼠模型。 /IDH 2 R172 K)和具有滤泡辅助性T细胞(TFH)表型的鼠淋巴瘤。 此外,我们产生了几种具有IDH 2 R172和/或TET 2突变的AITL的患者来源的异种移植物(PDX)。 我们假设T细胞中TET 2的缺乏改变了DNA甲基化谱,导致T细胞的DNA甲基化水平改变。 有利于TFH细胞分化和克隆扩增的遗传程序, 随后的命中,包括IDH 2 R172突变,这将进一步改变表观基因组和致癌基因, TFH -细胞转化的途径。我们将确定这些遗传病变在T细胞中的确切作用。 分化和AITL发病机制。我们还使用CRISPR/CAS9编辑了正常人CD 4 + T细胞, 产生TET 2-/-T细胞用于鼠模型的功能分析和交叉验证。由于TET 2突变在 造血干/祖细胞(HSPC)在一些AITL,TET 2缺陷的T细胞和基质细胞之间的相互作用 将探索淋巴瘤发生过程中的细胞。我们将测试治疗干预的有效性,包括 用于TET 2缺乏的脱甲基化剂和用于TET 2/IDH 2双重的IDH 2抑制剂和/或谷氨酰胺消耗 小鼠模型中的突变肿瘤和AITL的PDX。为实现这一目标,计划实现三个目标: 具体目标1:确定Tet 2缺陷介导T细胞转化的机制,以及Tet 2缺陷介导T细胞转化的机制。 Tet 2突变在淋巴瘤发生中的作用 具体目的2:阐明Tet 2和IDH 2 R172 K突变在AITL发病机制中的作用机制。 具体目的3:评价靶向Tet 2和IDH 2 R172介导的致癌机制的疗法 突变。 我们的长期研究目标是通过整合功能性表观基因组学, 使用体外修饰的人T细胞、患者样品和相关鼠模型的方法, 有希望的新的治疗靶点,可以在PDX模型中进行临床前测试。

项目成果

期刊论文数量(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。
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:
    $ 47.86万
  • 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:
    $ 47.86万
  • 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:
    $ 47.86万
  • 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:
    $ 47.86万
  • 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:
    10299140
  • 财政年份:
    2021
  • 资助金额:
    $ 47.86万
  • 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:
    $ 47.86万
  • 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:
    $ 47.86万
  • 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:
    $ 47.86万
  • 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:
    $ 47.86万
  • 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:
    $ 47.86万
  • 项目类别:
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