Molecular Pathogenesis & Therapy of JAK2 V617F-induced Myeloproliferative Disease

分子发病机制

• 批准号: 7468120
• 负责人: RICHARD A. VAN ETTEN
• 金额: $ 40.25万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7468120
• 关键词: A Mouse; Acute leukemia; Address; Anemia; Antibodies; Bcr-Abl tyrosine kinase; Biological Assay; Biological Models; Biology; Bleeding time procedure; Blood Clot; Blood Coagulation Disorders; Blood Platelets; Blood coagulation; Bone Marrow; Cells; Cessation of life; Chronic Myeloid Leukemia; Chronic Myeloproliferative Disorder; Clinical; Coagulation Process; Commit; Cytogenetics; Development; Disease; Disease remission; Drug Delivery Systems; Erythrocytes; Erythroid; Erythropoietin Receptor; Event; Functional disorder; Genetic; Goals; Hemorrhage; Hemorrhagic Thrombocythemia; Hemostatic Agents; Hemostatic function; Human; Imatinib; Inbred Strains Mice; Increased Red Cell Mass; JAK2 gene; Knowledge; Laboratories; Lead; Leukocytes; Leukocytosis; Megakaryocytes; Modeling; Molecular; Morbidity - disease rate; Mus; Mutation; Myelofibrosis; Myeloid Leukemia; Myeloproliferative disease; Myelosuppressive Therapy; Neutrophilia; Pancytopenia; Pathogenesis; Pathway interactions; Patients; Phase; Philadelphia Chromosome; Plasma; Platelet Count measurement; Polycythemia; Polycythemia Vera; Primary Myelofibrosis; Protein Tyrosine Kinase; Range; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Reticulocytosis; Role; Signal Pathway; Signaling Molecule; Somatic Mutation; Stem cells; Supportive care; Tail; Testing; Therapeutic; Therapeutic Effect; Thrombosis; Tissues; Transfusion; Transplantation; Venous blood sampling; abl Oncogene; base; bcr-abl Fusion Proteins; human disease; human study; in vivo; inhibitor/antagonist; kinase inhibitor; leukemia; mouse model; neutrophil; progenitor; research study; retroviral transduction; self-renewal; src-Family Kinases; therapeutic target

DESCRIPTION (provided by applicant): Chronic myeloid leukemia (CML) is a myeloproliferative disease (MPD) associated with BCR-ABL, an activated tyrosine kinase that is the product of the Philadelphia chromosome. A mouse model of CML, where BCR-ABL is expressed by retroviral bone marrow transduction and transplantation, demonstrated that BCR-ABL is the direct cause of CML, and motivated the development of imatinib, an ABL kinase inhibitor that has revolutionized the treatment of CML patients. Polycythemia vera (PV), essential thromobocythemia (ET), and chronic idiopathic myelofibrosis (CIMF) are MPDs that are as prevalent as CML, but their pathogenesis is unclear, and their clinical course is complicated by bleeding, thrombosis, and progression to acute leukemia or bone marrow failure. Current therapy for these MPDs is also inadequate, ranging from phlebotomy and myelosuppressive therapy for PV and ET, to transfusions and supportive care for CIMF. Recently, a somatic activating mutation (V617F) in the JAK2 tyrosine kinase was discovered in most patients with PV and some patients with ET and CIMF. However, the role of JAK2 V617F in the pathogenesis and potential therapy of these diseases is not known. A mouse retroviral transduction/transplantation model of MPD induced by JAK2 V617F has recently been developed by our laboratory. Using the model, it has been demonstrated that JAK2 V617F recapitulates the entire spectrum of erythroid abnormalities of PV in mice, implicating it as the direct and principal cause of human PV. In this application, this model system will be used to address some fundamental questions about the molecular pathogenesis and therapy of JAK2 V617F-induced MPD that would be difficult or impossible to approach through human studies. Specifically, the application proposes to: (1) use a genetic approach to determine the pathways downstream of JAK2 V617F that are required for MPD, with the ultimate goal of validating additional therapeutic targets; and (2) test the therapeutic activity of molecularly targeted drugs in JAK2 V617F-induced MPD, including candidate JAK2 inhibitors. These experiments will yield new knowledge about the biology and treatment of this important group of MPDs, and should provide important information to guide the clinical development of JAK2 kinase inhibitors and other molecularly targeted therapies for MPD. PROJECT NARRATIVE: Polycythemia vera (PV) is a human disease where too many red blood cells are produced. Current therapy for PV is inadequate due to blood clotting problems and development of leukemia. In this proposal, a mouse model of PV will be used to better understand the basic cause of PV, and to test new treatments for the disease, which could lead to better treatments for PV patients.

描述（由申请人提供）：慢性髓性白血病（CML）是一种与BCR-ABL相关的骨髓增生性疾病（MPD）， BCR-ABL是一种活化的酪氨酸激酶，是费城染色体的产物。在CML小鼠模型中，BCR-ABL通过逆转录病毒骨髓转导和移植表达，表明BCR-ABL是CML的直接原因，并推动了ABL激酶抑制剂伊马替尼（imatinib）的开发，该抑制剂彻底改变了CML患者的治疗。真性红细胞增多症（PV）、原发性血小板增多症（ET）和慢性特发性骨髓纤维化（CIMF）是与CML一样普遍的MPDs，但其发病机制尚不清楚，其临床病程复杂，可伴有出血、血栓形成，并进展为急性白血病或骨髓衰竭。目前对这些mpd的治疗也不充分，从静脉切开术和骨髓抑制治疗PV和ET，到输血和CIMF的支持治疗。近年来，在大多数PV患者以及部分ET和CIMF患者中发现JAK2酪氨酸激酶的体细胞激活突变（V617F）。然而，JAK2 V617F在这些疾病的发病机制和潜在治疗中的作用尚不清楚。我们实验室最近建立了一种由JAK2 V617F诱导的MPD小鼠逆转录病毒转导/移植模型。使用该模型，已经证明JAK2 V617F概括了小鼠红细胞PV异常的整个谱，这表明它是人类PV的直接和主要原因。在这项应用中，该模型系统将用于解决一些关于JAK2 v617f诱导的MPD的分子发病机制和治疗的基本问题，这些问题很难或不可能通过人体研究来解决。具体而言，该申请建议：(1)使用遗传方法确定MPD所需的JAK2 V617F下游通路，最终目标是验证其他治疗靶点；(2)测试分子靶向药物对JAK2 v617f诱导的MPD的治疗活性，包括候选JAK2抑制剂。这些实验将产生关于这一重要MPD群体的生物学和治疗的新知识，并为指导JAK2激酶抑制剂和其他MPD分子靶向治疗的临床开发提供重要信息。