Pathogenesis & Therapy of 8p11 Leukemia/Lymphoma

点击翻译按钮获取中文摘要

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.