Pathogenesis & Therapy of 8p11 Leukemia/Lymphoma

发病

• 批准号: 7048689
• 负责人: RICHARD A. VAN ETTEN
• 金额: $ 32.63万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7048689
• 关键词: biological signal transduction; blood /lymphatic pharmacology; blood disorder chemotherapy; bone marrow transplantation; chromosome translocation; eosinophilia; fibroblast growth factor; flow cytometry; gene expression; growth factor receptors; immunoprecipitation; kinase inhibitor; laboratory mouse; leukemia; lymphoma; pathologic process; phosphatidylinositol 3 kinase; phosphorylation; polymerase chain reaction; protein tyrosine kinase; western blottings

DESCRIPTION (provided by applicant): 8p11 stem cell leukemia/lymphoma syndrome, also known as 8p11 myeloproliferative syndrome (EMS), is a novel hematological malignancy characterized by chronic myeloproliferative disease, eosiniphilia, and non-Hodgkin's lymphoma. Current therapy for this disease is inadequate. The malignant cells from EMS patients have acquired chromosomal translocations involving the fibroblast growth factor receptor-1 (FGFR1) gene on 8p11 and express fusions of different N-terminal partner proteins with the tyrosine kinase domain of FGFR1. However, whether FGFR1 fusion proteins play a role in 8p11 syndrome and the molecular mechanisms underlying the pathogenesis of this disease are unknown. Recently, it has been demonstrated that different FGFR1 fusion proteins induce distinct leukemia/lymphoma syndromes in a mouse retroviral bone marrow transduction/transplantation model. These results implicate FGFR1 fusion tyrosine kinases as the direct cause of these malignancies and provide an accurate and quantitative animal model. In this application, this model system will be utilized to define the molecular pathogenesis of 8p11 leukemia/lymphoma syndrome and test targeted therapies for this disease. The first Aim will define the critical signaling pathways and the molecular mechanisms of induction of EMS-like disease in mice by the ZNF198-FGFR1 fusion tyrosine kinase, product of the (8;13) translocation in human 8pl 1 syndrome. This will be accomplished through biochemical analyses in Ba/F3 cells and primary leukemia cells from mice, studies with ZNF198-FGFR1 mutants, and use of mice with targeted mutations in signaling molecules. In the second Aim, the hematologic malignancies induced in mice by other FGFR1 fusions found in 8p11 syndrome, including FOP-FGFR1 and CEP110-FGFR1, will be characterized. The goal of the third Aim is preclinical testing of molecularly targeted therapeutic agents for 8p11 syndrome, comparing the antileukemic activity of several different FGFR1 kinase inhibitors in the mouse model of ZNF198-FGFR1- induced leukemia/lymphoma, and testing combinations of kinase inhibitors with drugs targeting essential downstream pathways identified in Aim 1. Collectively, these studies will yield important new knowledge about the pathogenesis and treatment of 8p11 syndrome that will also be valuable in extending targeted therapies to other hematologic malignancies and to solid tumors.

描述(申请人提供)：8p11干细胞白血病/淋巴瘤综合征，也称为8p11骨髓增殖性综合征(EMS)，是一种新的血液系统恶性肿瘤，以慢性骨髓增生性疾病、嗜酸性粒细胞增多症和非霍奇金淋巴瘤为特征。目前对这种疾病的治疗是不够的。EMS患者的恶性细胞在8p11上获得了涉及成纤维细胞生长因子受体-1(FGFR1)基因的染色体易位，并表达了不同N末端伴侣蛋白与FGFR1的酪氨酸激酶结构域的融合。然而，FGFR1融合蛋白是否在8p11综合征中起作用以及该疾病发病的分子机制尚不清楚。最近，已经证明不同的FGFR1融合蛋白在小鼠逆转录病毒骨髓转导/移植模型中诱导不同的白血病/淋巴瘤综合征。这些结果表明FGFR1融合酪氨酸激酶是这些恶性肿瘤的直接原因，并提供了一个准确和定量的动物模型。在这项应用中，该模型系统将用于确定8p11白血病/淋巴瘤综合征的分子发病机制，并测试针对该疾病的靶向治疗。第一个目标将确定ZNF198-FGFR1融合酪氨酸激酶诱导小鼠EMS样疾病的关键信号通路和分子机制。ZNF198-FGFR1融合酪氨酸激酶是人类8PL 1综合征(8；13)易位的产物。这将通过对小鼠的BA/F3细胞和原代白血病细胞进行生化分析，研究ZNF198-FGFR1突变体，以及使用具有信号分子靶向突变的小鼠来实现。在第二个目标中，将描述8p11综合征中发现的其他FGFR1融合导致的小鼠血液系统恶性肿瘤，包括FOP-FGFR1和CEP110-FGFR1。第三个目标是对8p11综合征的分子靶向治疗药物进行临床前测试，比较几种不同的FGFR1激酶抑制剂在ZNF198-FGFR1诱导的白血病/淋巴瘤小鼠模型中的抗白血病活性，并测试激酶抑制剂与目标1中确定的针对关键下游通路的药物的组合。总的来说，这些研究将产生关于8p11综合征的发病机制和治疗的重要新知识，这也将对将靶向治疗扩展到其他血液系统恶性肿瘤和实体瘤具有价值。