Molecular Pathogenesis of Two Newly Defined Major Subgroups of PTCL

PTCL 两个新定义的主要亚群的分子发病机制

• 批准号: 10237158
• 负责人: Javeed Iqbal
• 金额: $ 40.88万
• 依托单位: MAYO CLINIC ARIZONA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-19 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10237158
• 关键词: 1-Phosphatidylinositol 3-Kinase; Animal Model; Bioinformatics; Biological; Biology; Biometry; Cell Line; Classification; Clinical; Complex; Custom; DNA Sequence Alteration; Data; Development; Diagnosis; Diagnostic; Diagnostic Procedure; Formalin; GATA3 gene; Gene Expression; Gene Expression Profiling; Genes; Genetic; Genomics; Goals; Heterogeneity; Human; Incidence; Inferior; Intention; Lesion; Lymphoid; Lymphoma; Metabolic; Modeling; Molecular; Molecular Diagnosis; Molecular Profiling; Morphology; Mus; Mutation; Non-Hodgkin' s Lymphoma; Oncogenic; Outcome; PTEN gene; Paraffin Embedding; Pathogenesis; Pathology; Pathway interactions; Patient risk; Patients; Pattern; Peripheral; Pre-Clinical Model; Prognosis; Randomized Clinical Trials; Refractory; Relapse; Research; Role; Specific qualifier value; Subgroup; T cell differentiation; T-Cell Lymphoma; T-Cell Transformation; T-Lymphocyte; TP53 gene; Testing; Therapeutic; Tissue Embedding; Transcript; Xenograft Model; base; cohort; driver mutation; effective therapy; efficacy evaluation; efficacy testing; exome sequencing; functional genomics; gene function; genome integrity; genomic locus; improved; mRNA Expression; mTOR Inhibitor; mouse model; novel; novel therapeutic intervention; novel therapeutics; patient derived xenograft model; prognostic; risk stratification; targeted agent; therapeutic target; transcriptome sequencing; tumor

Peripheral T-cell Lymphoma (PTCL) encompasses a heterogonous group of clinically aggressive entities. Using current diagnostic approaches, more than a third cannot be classified and are designated as PTCL-not otherwise specified (PTCL-NOS). Using gene expression profiling (GEP), we delineated two novel major molecular subgroups in PTCL-NOS with distinct clinical and biological features. The first (PTCL-GATA3) is characterized by high expression of GATA3, a master regulator of T helper2 (TH2) differentiation and its target genes, whereas the second (PTCL-TBX21) is characterized by high expression of TBX21, master regulator of TH1 differentiation and its target genes, with the former showing significantly worse outcome. Preliminary genetic characterizations showed distinct patterns of chromosomal copy number abnormalities (CNAs) associated with significant enrichment of distinct oncogenic pathways. The long-term goal of the research is to define the mechanisms that determine the biology of these subgroups with the intention of identifying new targets and strategies for effective treatment, with special emphasis on the PTCL-GATA3 subgroup. This goal will be accomplished through three Specific Aims: (1) to determine the mutational landscape of the PTCL- GATA3 and PTCL-TBX21 subgroups. We hypothesize that deciphering the genetic mutational landscape of PTCL-GATA3 and PTCL-TBX21 will delineate the mechanistic basis of the differences in biology and clinical- outcome. We will perform whole exome- and RNA-sequencing (WES and RNA-seq) analysis on a well-defined cohort of PTCLs. A targeted capture panel will be established based on WES data to further determine the mutational incidence using formalin-fixed paraffin-embedded tissue (FFPET) in a large PTCL cohort including relapsed/refractory PTCL; (2) to delineate the role of combined PTEN and p53 loss in the pathobiology of the PTCL-GATA3 subgroup. We previously identified frequent co-occurrence of deletions of genomic loci encompassing pten and p53 in the PTCL-GATA3 subgroup but not in the PTCL-TBX21 subgroup. These genetic lesions may have functional consequences other than their canonical role in regulating the phosphatidylinositol 3-kinase (PI3K) pathway and genomic integrity. We hypothesize that pten and p53 loss cooperates in the oncogenic transformation of T-cells partly through deregulation of T cell differentiation. We will use both murine models and genetically modified human T-cells for this study; (3) to evaluate treatments targeting activated oncogenic pathways in the PTCL-GATA3 subgroup. No representative cell lines or animal models of poorest prognosis, PTCL-GATA3, subgroup are currently available. We hypothesize that well characterized PTCL PDTX models can serve as pre-clinical models for evaluating the efficacy of novel drugs in cases with dual pten/p53 loss. This Project will use Pathology Core 1, Biostatistics/Bioinformatics Core 4, Pre-Clinical Models and Therapeutics Core 3, and Functional Genomics Core 2 to accomplish these Aims.

周围T细胞淋巴瘤（PTCL）涵盖了临床上侵略性实体的异质组。 使用当前的诊断方法，三分之一以上不能分类，并被指定为PTCL-NOT 否则指定（PTCL-NOS）。使用基因表达谱分析（GEP），我们描绘了两个新的专业 具有不同临床和生物学特征的PTCL-NOS中的分子亚组。第一个（PTCL-GATA3）是 以高表达GATA3的高表达为特征，GATA3是T Helper2（TH2）分化的主要调节剂及其目标 基因，而第二个（PTCL-TBX21）的特征是TBX21高表达， Th1分化及其靶基因，前者显示出明显较差的结果。初步的 遗传特征显示出不同的染色体拷贝数异常的模式（CNA） 与明显的不同致癌途径的富集相关。研究的长期目标是 定义确定这些亚组生物学的机制，目的是识别新的 有效治疗的目标和策略，特别强调了PTCL-GATA3亚组。这个目标 将通过三个特定目的完成：（1）确定PTCL-的突变景观 GATA3和PTCL-TBX21亚组。我们假设该破译的遗传突变景观 PTCL-GATA3和PTCL-TBX21将描述生物学和临床差异的机械基础 结果。我们将对明确定义 PTCL的队列。将根据WES数据建立目标捕获面板，以进一步确定 使用福尔马林固定石蜡包裹的组织（FFPET）的突变发生率，包括大型PTCL队列 复发/难治性PTCL; （2）描述PTEN和p53损失在病理生物学中的作用 PTCL-GATA3子组。我们先前识别出基因组基因局缺失的频繁同时出现 在PTCL-GATA3子组中包含PTEN和p53，但不包含PTCL-TBX21子组中的PTEN和p53。这些 遗传病变可能具有功能后果，而不是其规范作用在调节 磷脂酰肌醇3-激酶（PI3K）途径和基因组完整性。我们假设PTEN和p53损失 通过放松T细胞分化的放松调节，在T细胞的致癌转化中进行了合作。我们 这项研究将使用鼠模型和转基因的人类T细胞； （3）评估治疗 靶向PTCL-GATA3亚组中激活的致癌途径。没有代表性的细胞系或动物 当前有最糟糕的预后，PTCL-GATA3，亚组的模型。我们假设这很好 表征的PTCL PDTX模型可以用作评估新药物在 双重PTEN/p53损失的病例。该项目将使用病理学核心1，生物统计学/生物信息学核心4， 临床前模型和治疗核心3，以及功能基因组学核心2来完成这些 目标。