Pathogenesis & Therapy of 8p11 Leukemia/Lymphoma

发病

• 批准号: 7201578
• 负责人: RICHARD A. VAN ETTEN
• 金额: $ 31.68万
• 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/7201578
• 关键词: 8p11; Animal Model; Biochemical; Biological Models; Bone Marrow; Cells; Chimeric Proteins; Chromosomal translocation; Chronic Myeloproliferative Disorder; Clinical Research; Disease; Drug Delivery Systems; FGFR1 gene; FUS-1 Protein; Fibroblast Growth Factor Receptor 1; Goals; Hematologic Neoplasms; Hematological Disease; Human; Knowledge; Malignant Neoplasms; Modeling; Molecular; Mus; Mutation; N-terminal; Non-Hodgkin' s Lymphoma; Pathogenesis; Pathway interactions; Patients; Play; Preclinical Testing; Protein Tyrosine Kinase; Proteins; Role; Signal Pathway; Signaling Molecule; Solid Neoplasm; Syndrome; Testing; Therapeutic Agents; Transplantation; Tyrosine Kinase Domain; cancer cell; kinase inhibitor; leukemia; leukemia/lymphoma; leukemic stem cell; mouse model; mutant; novel

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（由申请人提供）：8P11干细胞白血病/淋巴瘤综合征，也称为8P11脊髓增生性综合征（EMS），是一种新型血液学恶性肿瘤，其特征是以慢性骨髓增生性疾病，eosiniphilia和Non-Hodgkin的淋巴瘤为特征。目前对这种疾病的疗法不足。来自EMS患者的恶性细胞已获得8P11上涉及成纤维细胞生长因子受体1（FGFR1）基因的染色体易位，并与FGFR1的酪氨酸激酶结构域的不同N末端伴侣蛋白的表达融合。但是，FGFR1融合蛋白是否在8p11综合征中起作用，以及该疾病发病机理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。这些结果暗示FGFR1融合酪氨酸激酶是这些恶性肿瘤的直接原因，并提供了准确和定量的动物模型。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理和该疾病的测试靶向疗法。第一个目的将定义通过ZnF198-FGFR1融合酪氨酸激酶（人类8PL 1综合征（8; 13）易位的产物）ZnF198-FGFR1融合酪氨酸激酶的关键信号通路和EMS样疾病诱导EMS样疾病的分子机制。这将通过在小鼠的BA/F3细胞和原发性白血病，对ZnF198-FGFR1突变体的研究以及在信号分子中使用靶向突变的小鼠的生化分析来实现。在第二个目标中，将表征8p11综合征中发现的其他FGFR1融合物在小鼠中诱导的血液系统恶性肿瘤，包括FOP-FGFR1和CEP110-FGFR1。第三个目标的目的是对8p11综合征的分子靶向治疗剂进行临床前测试，比较了ZnF198-FGFR1的小鼠模型中几种不同的FGFR1激酶抑制剂的抗肺化活性研究将产生有关8P11综合征的发病机理和治疗的重要新知识，这些知识也将在将靶向疗法扩展到其他血液系统恶性肿瘤和实体肿瘤中也很有价值。