Pathogenesis & Therapy of 8p11 Leukemia/Lymphoma
发病
基本信息
- 批准号:6879757
- 负责人:
- 金额:$ 33.42万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2004
- 资助国家:美国
- 起止时间:2004-04-01 至 2009-03-31
- 项目状态:已结题
- 来源:
- 关键词:biological signal transductionblood /lymphatic pharmacologyblood disorder chemotherapybone marrow transplantationchromosome translocationeosinophiliafibroblast growth factorflow cytometrygene expressiongrowth factor receptorsimmunoprecipitationkinase inhibitorlaboratory mouseleukemialymphomapathologic processphosphatidylinositol 3 kinasephosphorylationpolymerase chain reactionprotein tyrosine kinasewestern blottings
项目摘要
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骨髓增殖综合征(EMS),是一种以慢性骨髓增殖性疾病、嗜酸性粒细胞增多症和非霍奇金淋巴瘤为特征的新型血液恶性肿瘤。目前对这种疾病的治疗是不够的。来自 EMS 患者的恶性细胞已获得涉及 8p11 上成纤维细胞生长因子受体 1 (FGFR1) 基因的染色体易位,并表达不同 N 末端伙伴蛋白与 FGFR1 酪氨酸激酶结构域的融合。然而,FGFR1融合蛋白是否在8p11综合征中发挥作用以及该疾病发病机制的分子机制尚不清楚。最近,已证明不同的 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,并提供了准确且定量的动物模型。在此应用中,该模型系统将用于定义 8p11 白血病/淋巴瘤综合征的分子发病机制并测试该疾病的靶向治疗。第一个目标将定义 ZNF198-FGFR1 融合酪氨酸激酶(人类 8pl 1 综合征中 (8;13) 易位的产物)在小鼠中诱导 EMS 样疾病的关键信号通路和分子机制。这将通过对 Ba/F3 细胞和小鼠原发性白血病细胞的生化分析、ZNF198-FGFR1 突变体的研究以及使用信号分子中具有靶向突变的小鼠来完成。在第二个目标中,将描述 8p11 综合征中发现的其他 FGFR1 融合(包括 FOP-FGFR1 和 CEP110-FGFR1)在小鼠中诱导的血液恶性肿瘤的特征。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 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药物的组合针对目标 1 中确定的重要下游途径。总的来说,这些研究将产生有关 8p11 综合征发病机制和治疗的重要新知识,这将在将靶向治疗扩展到其他血液恶性肿瘤和实体瘤方面也很有价值。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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RICHARD A. VAN ETTEN其他文献
RICHARD A. VAN ETTEN的其他文献
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{{ truncateString('RICHARD A. VAN ETTEN', 18)}}的其他基金
Project 3: Modeling Malignant Myelopoiesis to Increase Efficacy of Targeted Leukemia Therapy
项目3:恶性骨髓细胞生成建模以提高白血病靶向治疗的疗效
- 批准号:
10392899 - 财政年份:2018
- 资助金额:
$ 33.42万 - 项目类别:
Molecular Pathogenesis & Therapy of JAK2 V617F-induced Myeloproliferative Disease
分子发病机制
- 批准号:
7802864 - 财政年份:2008
- 资助金额:
$ 33.42万 - 项目类别:
Molecular Pathogenesis & Therapy of JAK2 V617F-induced Myeloproliferative Disease
分子发病机制
- 批准号:
8043589 - 财政年份:2008
- 资助金额:
$ 33.42万 - 项目类别:
Molecular Pathogenesis & Therapy of JAK2 V617F-induced Myeloproliferative Disease
分子发病机制
- 批准号:
7468120 - 财政年份:2008
- 资助金额:
$ 33.42万 - 项目类别:
Molecular Pathogenesis & Therapy of JAK2 V617F-induced Myeloproliferative Disease
分子发病机制
- 批准号:
8043589 - 财政年份:2008
- 资助金额:
$ 33.42万 - 项目类别:
Molecular Pathogenesis & Therapy of JAK2 V617F-induced Myeloproliferative Disease
分子发病机制
- 批准号:
7597145 - 财政年份:2008
- 资助金额:
$ 33.42万 - 项目类别:
Molecular Pathogenesis & Therapy of JAK2 V617F-induced Myeloproliferative Disease
分子发病机制
- 批准号:
8241994 - 财政年份:2008
- 资助金额:
$ 33.42万 - 项目类别:
Molecular Pathogenesis & Therapy of JAK2 V617F-induced Myeloproliferative Disease
分子发病机制
- 批准号:
8241994 - 财政年份:2008
- 资助金额:
$ 33.42万 - 项目类别:
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