Molecular Pathogenesis & Therapy of JAK2 V617F-induced Myeloproliferative Disease

描述(申请人提供)：慢性髓系白血病(CML)是一种与bcr-abl相关的骨髓增生性疾病(MPD)，bcr-abl是一种激活的酪氨酸激酶，是费城染色体的产物。通过逆转录病毒骨髓转导和移植表达BCR-ABL的CML小鼠模型证明，BCR-ABL是CML的直接原因，并推动了ABL激酶抑制剂伊马替尼的开发，使CML患者的治疗发生了革命性的变化。真性红细胞增多症(PV)、原发性红细胞增多症(ET)和慢性特发性骨髓纤维化(CIMF)是与CML一样常见的MPD，但其发病机制尚不清楚，其临床过程复杂，常伴有出血、血栓形成和进展为急性白血病或骨髓衰竭。目前对这些MPD的治疗也是不够的，从PV和ET的静脉切开和骨髓抑制治疗，到CIMF的输血和支持性护理。最近，在大多数PV患者和部分ET和CIMF患者中发现了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。本实验室最近建立了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PV红系异常的全部光谱，暗示它是人类PV的直接和主要原因。在这个应用中，这个模型系统将被用来解决JAK2 V617F诱导的MPD的分子发病机制和治疗的一些基本问题，这些问题是很难或不可能通过人类研究来解决的。具体地说，该申请建议：(1)使用遗传方法来确定MPD所需的JAK2 V617F下游的途径，最终目标是验证其他治疗靶点；以及(2)测试分子靶向药物在JAK2 V617F诱导的MPD中的治疗活性，包括候选JAK2抑制剂。这些实验将产生关于这一重要组MPD的生物学和治疗的新知识，并将为指导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。 项目简介：真性红细胞增多症(PV)是一种人类疾病，会产生太多的红细胞。由于血液凝结问题和白血病的发展，目前对PV的治疗是不够的。在这项提案中，将使用PV的小鼠模型来更好地了解PV的基本原因，并测试这种疾病的新治疗方法，这可能会导致对PV患者的更好治疗。

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.