Molecular Classification of Anaplastic Large Cell Lymphoma

间变性大细胞淋巴瘤的分子分类

• 批准号: 10237160
• 负责人: Andrew Lewis Feldman
• 金额: $ 59.48万
• 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/10237160
• 关键词: Antitumor Response; BHLH Protein; Bioinformatics; Biological; Biological Markers; Biology; Biometry; Case Series; Cells; Chromosome abnormality; Classification; Clinic; Clinical; Clinical Management; Complement; DNA; DNA Methylation; DUSP22 gene; Data; Data Set; Development; Diagnosis; Disease; Drug Design; Drug Targeting; Environment; Gene Expression; Gene Expression Profile; Gene Mutation; Genes; Genetic; Genomics; Geography; Goals; Growth; Helix-Turn-Helix Motifs; Hematology; Heterogeneity; Immune response; Immune system; Immunohistochemistry; Individual; Infrastructure; Investigational Therapies; Ki-1 Large-Cell Lymphoma; Knowledge; Laboratories; Lead; Letters; Lymphocyte; Lymphoma; Malignant Neoplasms; Mass Spectrum Analysis; Methodology; Methylation; Molecular; Molecular Diagnosis; Molecular Profiling; Molecular Target; Mutation; Oncology; Outcome; Paraffin; Pathogenesis; Pathology; Pathway interactions; Patients; Pattern; Pre-Clinical Model; Prognosis; Proteins; Proteomics; Regulator Genes; Reporting; Research Personnel; Risk; Role; STAT3 gene; Stat3 protein; Subgroup; Survival Rate; System; Systems Biology; T-Cell Lymphoma; Technology; Testing; Therapeutic; Tissues; Transcend; Translational Research; Tumor Tissue; United States; Up-Regulation; Work; base; cancer testis antigen; clinical Diagnosis; clinical biomarkers; clinical heterogeneity; cohort; digital; ethnic diversity; functional genomics; genetic testing; improved; individual patient; individualized medicine; inhibitor/antagonist; innovation; insight; methylation pattern; methylome; methylomics; molecular phenotype; molecular subtypes; multidisciplinary; new therapeutic target; novel; novel therapeutics; patient subsets; personalized diagnostics; personalized medicine; phosphoproteomics; prognostic; programs; protein activation; protein expression; racial and ethnic; response; success; targeted treatment; therapeutic target; tissue resource; tool; transcriptome sequencing; transcriptomics; tumor; tumor growth

T-cell lymphomas represent a heterogeneous and understudied group of malignancies of the immune system with poor response to standard therapy in most cases. However, subsets of patients have excellent outcomes for unknown reasons. The goal of this project is to develop personalized medicine strategies for patients with anaplastic large cell lymphoma (ALCL), one of the most common types of T-cell lymphoma. Specifically, we will use genomic discovery to develop genetic tests that: (1) identify specific drug targets in tumor tissue and guide targeted therapy, and (2) distinguish highly aggressive tumors from less aggressive so that the intensity of therapy can be individualized. Currently, only one gene, ALK, is tested to classify ALCLs. Our team has identified chromosome abnormalities of two other genes in ALCL, DUSP22 and TP63. Five-year survival rates for ALCL patients with abnormal DUSP22 are 90%, compared to only 17% for patients with abnormal TP63. The reasons for this marked difference in survival remain unknown, and both groups of patients currently receive the same treatment. Furthermore, some ALCLs grow in response to a group of growth-promoting proteins collectively known as JAK-STAT3. Importantly, tumor growth caused by JAK-STAT3 can be blocked by drugs that target these proteins. However, the relationship between JAK-STAT3 proteins and DUSP22 and TP63 abnormalities has not been studied. In Aim 1, we will determine the relationship of DUSP22- and TP63- rearranged ALCLs to dysregulation of the JAK-STAT3 pathway using a combination of RNA sequencing to examine gene expression and mass spectrometry to assess protein activation. We anticipate developing laboratory tests that differentiate these distinct types of ALCL, and also identifying key growth-promoting proteins that could lead to new targeted therapies for ALCLs that lack JAK-STAT. In Aim 2, we will identify the spectrum and role of mutations in ALCL. Specifically, we have discovered mutations that alter proteins called basic helix-loop-helix (bHLH) transcription factors that are key regulators of gene expression in lymphocytes. We anticipate that bHLH gene mutations will cooperate with other abnormalities (e.g., DUSP22) to promote tumor growth, and that understanding this cooperation will lead to new therapies for ALCLs. In Aim 3, we will characterize the methylome of DUSP22-rearranged and other ALCLs to identify key differences in DNA methylation, a major factor controlling the specific genes that are expressed in a given cell. Our data suggest that ALCLs vary widely in their degree of DNA methylation. We anticipate finding that the methylation pattern in ALCLs with DUSP22 abnormalities leads to expression of proteins known as cancer-testis antigens, suggesting that these tumors may be particularly sensitive to therapies that enhance antitumor responses of the host immune system. In contrast, we anticipate that ALCLs with excessive methylation will respond to drugs designed to reduce DNA methylation. All 3 Project Aims will utilize the Pathology and Bioinformatics Cores. Aim 2 will utilize the Functional Genomics and Preclinical Models and Therapeutics Cores.

T细胞淋巴瘤是一组异质性的、未被研究的免疫系统恶性肿瘤。 在大多数情况下对标准治疗的反应很差。然而，部分患者的预后很好。 原因不明。该项目的目标是为患有癌症的患者开发个性化的药物策略 间变性大细胞淋巴瘤(ALCL)，T细胞淋巴瘤最常见的类型之一。具体来说，我们 将利用基因组发现开发基因测试：(1)识别肿瘤组织中的特定药物靶点 引导靶向治疗，以及(2)区分高侵袭性肿瘤和低侵袭性肿瘤，使强度 治疗方法可以个体化。目前，只有一个基因alk被测试来对ALCL进行分类。我们队有 在ALCL中发现了另外两个基因dusp22和tp63的染色体异常。五年存活率 在dusp22异常的ALCL患者中有90%，而在tP63异常的患者中只有17%。 这种显著的存活率差异的原因尚不清楚，目前这两组患者 得到同样的待遇。此外，一些ALCL的生长是对一组促进生长的反应 统称为JAK-STAT3的蛋白质。重要的是，JAK-STAT3引起的肿瘤生长可以被阻断 通过靶向这些蛋白质的药物。然而，JAK-STAT3蛋白与dusp22和dusp22的关系 目前尚未对TP63异常进行研究。在目标1中，我们将确定dusp22-和tp63-的关系。 使用RNA测序的组合来重排ALCL以应对JAK-STAT3途径的失调 检测基因表达和质谱学以评估蛋白质的活性。我们期待着发展 区分这些不同类型的ALCL的实验室测试，并确定关键的促进生长 可以为缺乏JAK-STAT的ALCL带来新的靶向治疗的蛋白质。在目标2中，我们将确定 ALCL基因突变的谱系和作用。具体地说，我们发现了改变蛋白质的突变，称为 碱性螺旋-环-螺旋(BHLH)转录因子是淋巴细胞基因表达的关键调节因子。 我们预计bhlh基因突变将与其他异常(如dusp22)协同促进 肿瘤的生长，了解这种合作将导致ALCL的新疗法。在《目标3》中，我们将 鉴定dusp22重排和其他ALCL的甲基组以确定DNA中的关键差异 甲基化，控制特定基因在特定细胞中表达的主要因素。我们的数据显示 ALCL的DNA甲基化程度差异很大。我们预计会发现甲基化模式在 带有dusp22异常的ALCL导致被称为癌症-睾丸抗原的蛋白质的表达， 提示这些肿瘤可能对增强抗肿瘤反应的治疗特别敏感。 宿主免疫系统。相反，我们预计具有过度甲基化的ALCL将对 旨在减少DNA甲基化的药物。所有三个项目AIMS都将利用病理学和生物信息学 核心。AIM 2将利用功能基因组学和临床前模型和治疗核心。