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: 10477215
• 负责人: Javeed Iqbal
• 金额: $ 42.46万
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10477215
• 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 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; diagnostic strategy; 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.

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，超过三分之一的人无法分类，并被指定为PTCL-非 另有规定（PTCL-NOS）。使用基因表达谱（GEP），我们描绘了两个新的主要 PTCL-NOS的分子亚群具有不同的临床和生物学特征。第一个（PTCL-GATA 3）是 其特征在于高表达GATA 3，其是辅助性T细胞2（TH 2）分化的主要调节因子， 基因，而第二个（PTCL-TBX 21）的特征在于TBX 21的高表达，TBX 21是细胞增殖的主调节因子。 TH 1分化及其靶基因，前者表现出明显较差的结果。初步 遗传特征显示染色体拷贝数异常（CNAs）的不同模式 与显著富集不同的致癌途径相关。这项研究的长期目标是 定义决定这些亚组生物学的机制，目的是确定新的 有效治疗的目标和策略，特别强调PTCL-GATA 3亚组。这一目标 将通过三个具体目标来实现：（1）确定PTCL的突变景观- GATA 3和PTCL-TBX 21亚组。我们假设，破译基因突变景观， PTCL-GATA 3和PTCL-TBX 21将描述生物学和临床差异的机制基础。 结果。我们将对一个定义明确的基因组进行全外显子组和RNA测序（WES和RNA-seq）分析。 PTCL队列。将根据WES数据建立靶向捕获面板，以进一步确定 在一个大型PTCL队列中使用福尔马林固定石蜡包埋组织（FFPET）的突变发生率，包括 复发性/难治性PTCL;（2）描述组合的PTEN和p53丢失在复发性/难治性PTCL的病理生物学中的作用。 PTCL-GATA 3亚组。我们以前发现频繁的共同发生的基因组位点的缺失 包括PTCL-GATA 3亚组中的pten和p53，但不包括PTCL-TBX 21亚组中的pten和p53。这些 遗传损伤可能具有功能性后果，而不是它们在调节细胞凋亡中的典型作用。 磷脂酰肌醇3-激酶（PI 3 K）途径和基因组完整性。我们假设pten和p53的缺失 部分通过T细胞分化的失调在T细胞的致癌转化中起作用。我们 将使用鼠模型和遗传修饰的人T细胞进行这项研究;（3）评估治疗 靶向PTCL-GATA 3亚组中激活的致癌通路。无代表性细胞系或动物 最差预后模型PTCL-GATA 3亚组是目前可用的。我们假设 表征的PTCL PDTX模型可以用作评价新药在治疗中的功效的临床前模型。 pten/p53双重缺失例。本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，以实现这些目标 目标。