Novel role of STAT3 in NPM/ALK-induced oncogenesis

STAT3 在 NPM/ALK 诱导的肿瘤发生中的新作用

• 批准号: 7744684
• 负责人: MARIUSZ A. WASIK
• 金额: $ 29.94万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7744684
• 关键词: Affect; Apoptosis; B-Cell Lymphomas; Brain; Cell Cycle Progression; Cell Line; Cell Proliferation; Cell physiology; Cells; Cellular biology; Chimeric Proteins; DNA Modification Methylases; Deoxycytidine; Disease; Epigenetic Process; Family; Gene Expression; Gene Silencing; Gene Targeting; Genes; Genome; Glioblastoma; Goals; Human; Immune response; In Vitro; Inflammatory Pseudotumor; Intestines; Ki-1 Large-Cell Lymphoma; Lead; Lung Neoplasms; Lymphoma; Malignant - descriptor; Malignant Neoplasms; Mediating; Modality; Molecular; NPM1 gene; Neoplasms; Neuroblastoma; Non-Small-Cell Lung Carcinoma; Oncogenic; PTPN6 gene; Pathogenesis; Pattern; Phosphotransferases; Play; Pre-Clinical Model; Progress Reports; Protein Tyrosine Kinase; Proteins; Research; Retinoblastoma; Rhabdomyosarcoma; Role; STAT3 gene; STAT5A gene; Signal Pathway; Signal Transduction; Small Interfering RNA; Stream; Study Section; T-Cell Lymphoma; T-Lymphocyte; T-Lymphocyte Subsets; Tissues; Transfection; Transgenic Mice; Tumor Suppressor Genes; Validation; activating transcription factor; base; cancer cell; cancer type; cell motility; cell transformation; comparative; design; in vivo; inhibitor/antagonist; kinase inhibitor; member; mouse model; novel; preference; public health relevance; research study; small molecule; transcription factor; tumor; tumor growth; tumorigenesis; vector

DESCRIPTION (provided by applicant): This proposal is aimed at a better understanding of the oncogenic role of anaplastic large cell lymphoma kinase (ALK). ALK is aberrantly expressed (most frequently as the NPM/ALK fusion protein) and/or activated in a subset of human T-cell and B-cell lymphomas, inflammatory myofibroblastic tumors, subsets of non-small cell lung carcinoma, rhabdomyosarcoma, neuroblastoma, glioblastoma and retinoblastoma and, apparently, other malignancies. Whereas NPM/ALK is highly oncogenic, the exact mechanisms of the ALK-mediated cell transformation remain only partially elucidated. In this study we will examine these mechanisms by focusing on the key transcription factors activated by NPM/ALK: STAT3 and STAT5b including the role of STAT3 in induction of epigenetic gene silencing. We will also develop preclinical model of targeted therapy aimed at simultaneous disruption of the ALK/STAT-mediated cell signaling and ALK expression. To accomplish these goals we will: 1. Identify the genes regulated by NPM/ALK-STAT3 and NPM/ALK-STAT5b signaling pathways and examine the role of proteins encoded by the selected identified genes in the malignant cell transformation. 2. Examine the mechanisms of the STAT3-induced epigenetic silencing of the STAT5a gene. 3. Determine the effects of ALK and DNMT inhibitors on tumor growth in vitro and in vivo. This study should lead to further elucidation of pathogenesis of the ALK-driven neoplasms and may pave the road to novel, targeted therapies for these malignant disorders. Because the aberrant activation of STAT3 and STAT5 as well as the epigenetic silencing of tumor suppressor genes have been identified in the large spectrum of malignancies, results of this study may also have an impact on research and, prospectively, therapy of other types of cancer. PUBLIC HEALTH RELEVANCE: Understanding exact mechanisms of the aberrant activation of cell signal transduction by oncogenic tyrosine kinases such as NPM/ALK and the role of their down-stream signaling effector proteins such as STAT3 and STAT5 transcription factors should lead to novel treatment modalities based on selective inhibition of activity of the oncogenic kinase as well as its key effector proteins. Therefore, these studies may result in targeted therapies for NPM/ALK- expressing lymphomas and other malignancies expressing oncogenic form of the ALK tyrosine kinase. Given that aberrant STAT3 and STAT5 activation is present in many types of cancer, they may also impact on research pertaining to tumors unrelated to ALK.

描述（由申请人提供）：本提案旨在更好地了解间变性大细胞淋巴瘤激酶（ALK）的致瘤作用。ALK在人类t细胞和b细胞淋巴瘤、炎症性肌纤维母细胞肿瘤、非小细胞肺癌、横纹肌肉瘤、神经母细胞瘤、胶质母细胞瘤和视网膜母细胞瘤亚群以及其他恶性肿瘤中异常表达（最常见的是NPM/ALK融合蛋白）和/或被激活。虽然NPM/ALK是高度致癌的，但ALK介导的细胞转化的确切机制仍然只是部分阐明。在这项研究中，我们将通过关注NPM/ALK激活的关键转录因子：STAT3和STAT5b来研究这些机制，包括STAT3在诱导表观遗传基因沉默中的作用。我们还将开发靶向治疗的临床前模型，旨在同时破坏ALK/ stat介导的细胞信号传导和ALK表达。为实现这些目标，我们将：鉴定受NPM/ALK-STAT3和NPM/ALK-STAT5b信号通路调控的基因，并研究选定鉴定基因编码的蛋白在恶性细胞转化中的作用。2. 研究stat3诱导STAT5a基因表观遗传沉默的机制。3. 测定ALK和DNMT抑制剂在体内体外对肿瘤生长的影响。这项研究将导致进一步阐明alk驱动肿瘤的发病机制，并可能为这些恶性疾病的新型靶向治疗铺平道路。由于STAT3和STAT5的异常激活以及肿瘤抑制基因的表观遗传沉默已经在大量恶性肿瘤中被发现，因此本研究的结果也可能对其他类型癌症的研究和治疗产生影响。公共卫生相关性：了解致癌酪氨酸激酶（如NPM/ALK）异常激活细胞信号转导的确切机制及其下游信号效应蛋白（如STAT3和STAT5转录因子）的作用，应该导致基于选择性抑制致癌激酶及其关键效应蛋白活性的新治疗方式。因此，这些研究可能会导致针对表达NPM/ALK-的淋巴瘤和其他表达ALK酪氨酸激酶致癌形式的恶性肿瘤的靶向治疗。鉴于STAT3和STAT5的异常激活存在于许多类型的癌症中，它们也可能影响与ALK无关的肿瘤的研究。