Molecular Pathogenesis & Therapy in JAK2 V617F Myeloproliferative Disease

分子发病机制

• 批准号: 7860817
• 负责人: Virginia Zaleskas
• 金额: $ 12.83万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7860817
• 关键词: A Mouse; Acute leukemia; Address; Anemia; Bcr-Abl tyrosine kinase; Biological Assay; Biological Models; Biology; Bleeding time procedure; Blood Clot; Blood Platelets; Blood coagulation; Bone Marrow; Bone Marrow Transplantation; Cells; Chimeric Proteins; Chronic Myeloid Leukemia; Clinical; Cytogenetics; Development; Disease; Disease remission; Drug Delivery Systems; Erythrocytes; Erythroid; Erythropoietin Receptor; Event; Functional disorder; Genes; Genetic; Goals; Hematopoietic stem cells; Hemorrhage; Hemorrhagic Thrombocythemia; Hemostatic Agents; Hemostatic function; Human; Imatinib; JAK2 gene; Knowledge; Megakaryocytes; Modeling; Molecular; Mus; Mutation; Myelofibrosis; Myeloproliferative disease; Myelosuppressive Therapy; Pancytopenia; Pathogenesis; Pathway interactions; Patients; Phase; Philadelphia Chromosome; Plasma; Platelet Count measurement; Polycythemia; Polycythemia Vera; Primary Myelofibrosis; Protein Tyrosine Kinase; Quality of life; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Red Cell Mass result; Research Personnel; Reticulocytosis; Retroviral Vector; Role; Signal Pathway; Somatic Mutation; Supportive care; Tail; Technology; Testing; Therapeutic; Therapeutic Effect; Thrombosis; Transfusion; Transplantation; Venous blood sampling; Virginia; bcr-abl Fusion Proteins; human disease; improved; in vivo; inhibitor/antagonist; kinase inhibitor; leukemia; mouse model; neutrophil; novel; null mutation; programs; recombinase; research study; retroviral transduction; 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. 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. Polycythemia vera (PV) is a human disease where too many red blood cells are produced. Current treatment 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. These experiments have potential to improve the quality of life for PV patients.

描述（由申请人提供）： 慢性髓样白血病（CML）是与BCR-ABL相关的髓增生性疾病（MPD），BCR-ABL是一种活性酪氨酸激酶，是费城染色体的产物。 CML的小鼠模型，其中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，并激发了Imatinib的发展，Imatinib是一种ABL激酶抑制剂，该酶抑制剂已彻底改变了CML患者的治疗。多余细胞性vera（PV），必需的血栓细胞增多症（ET）和慢性特发性骨髓纤维化（CIMF）是MPD，它们与CML一样普遍，但它们的发病机理尚不清楚，它们的临床过程尚不清楚，并且由于出血，血栓形成，促进性和急症性白血病或骨骼质量失败而变得复杂。这些MPD的当前疗法也不足，范围从静脉切开术和PV和ET的骨髓抑制疗法到CIMF的输血和支持护理。最近，在大多数PV患者和一些ET和CIMF患者中发现了JAK2酪氨酸激酶中的体细胞激活突变（V617F）。但是，JAK2 V617F在这些疾病的发病机理和潜在治疗中的作用尚不清楚。最近已经开发了由JAK2 V617F诱导的MPD的小鼠逆转录/移植模型。使用该模型，已经证明JAK2 V617F概括了小鼠PV的整个红斑异常谱，这意味着它是人类PV的直接和主要原因。在此应用中，该模型系统将用于解决有关JAK2 V617F诱导的MPD的分子发病机理和治疗的一些基本问题，这些问题很难或不可能通过人类研究来解决。具体而言，该应用程序建议：（1）使用遗传方法来确定MPD所需的JAK2 V617F下游的途径，其最终目标是验证其他治疗靶标； （2）测试JAK2 V617F诱导的MPD中分子靶向药物的治疗活性，包括候选JAK2抑制剂。这些实验将产生有关这一重要MPD的生物学和治疗的新知识，并应提供重要信息，以指导JAK2激酶抑制剂的临床发展和其他分子靶向MPD的疗法。 Polycytheria Vera（PV）是一种人类疾病，在其中产生了太多的红细胞。由于血液凝结问题和白血病的发展，当前对PV的治疗不足。在此提案中，PV的小鼠模型将用于更好地了解PV的基本原因，并测试该疾病的新治疗方法。这些实验有可能改善光伏患者的生活质量。