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: 9788311
• 负责人: Javeed Iqbal
• 金额: $ 40.45万
• 依托单位: MAYO CLINIC ARIZONA
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9788311
• 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; Expression Profiling; 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; Randomized Clinical Trials; Refractory; Relapse; Research; Risk stratification; 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; actionable mutation; base; cohort; effective therapy; efficacy testing; exome sequencing; functional genomics; gene function; genome integrity; improved; mRNA Expression; mTOR Inhibitor; mouse model; novel; novel therapeutic intervention; novel therapeutics; outcome forecast; prognostic; 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.

外周T细胞淋巴瘤(PTCL)包括一组异质性的临床侵袭性实体。 使用目前的诊断方法，超过三分之一无法分类并被指定为PTCL-NOT 另有规定(PTCL-NOS)。利用基因表达谱(GEP)，我们描绘了两个新的主要 PTCL-NOS分子亚群具有明显的临床和生物学特征。第一个(PTCL-GATA3)是 以T辅助细胞2(TH2)分化主要调控因子GATA3的高表达为特征及其靶点 而第二个基因(PTCL-Tbx21)以Tbx21高表达为特征，Tbx21是Tbx21的主要调控因子 Th1分化及其靶基因，前者的预后明显较差。初步 遗传特征显示出明显的染色体拷贝数异常(CNA)模式。 与不同致癌途径的显著丰富有关。这项研究的长期目标是 定义决定这些亚群的生物学的机制，目的是确定新的 有效治疗的目标和战略，特别强调PTCL-GATA3亚组。这个目标 将通过三个具体目标来实现：(1)确定PTCL的突变格局-- GATA3和PTCL-Tbx21亚组。我们假设破译人类基因突变的图景 PTCL-GATA3和PTCL-Tbx21将描绘生物学和临床差异的机制基础-- 结果。我们将执行完整的外显子和RNA测序(WES和RNA-seq)分析 PTCL的队列。将根据WES数据建立有针对性的捕获小组，以进一步确定 福尔马林固定石蜡包埋组织(FFPET)在大型PTCL队列中的突变发生率，包括 目的：(2)阐明PTEN和P53联合缺失在卵巢癌病理生物学中的作用。 PTCL-GATA3亚群。我们之前发现了基因组基因座缺失的频繁共存 PTCL-GATA3亚组中包括PTEN和P53，但在PTCL-Tbx21亚组中不表达。这些 基因损伤可能会有功能后果，而不是它们在调节 磷脂酰肌醇3-激酶(PI3K)途径与基因组完整性我们假设PTEN和P53的缺失 在T细胞的致癌转化中合作，部分是通过放松对T细胞分化的调控。我们 将使用小鼠模型和转基因人类T细胞进行这项研究；(3)评估治疗方法 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 目前已有预后最差的PTCL-GATA3亚组模型。我们做了很好的假设 特征化的PTCL PDTX模型可作为评估新药疗效的临床前模型 PTEN/P53双重缺失5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和功能基因组学核心2实现这些 目标。