Identification of novel target genes for polycythemia vera (PV)

真性红细胞增多症（PV）新靶基因的鉴定

• 批准号: 8283603
• 负责人: Shaoguang Li
• 金额: $ 24.91万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-26 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8283603
• 关键词: Acute leukemia; Adverse drug effect; Adverse effects; Affect; Arachidonate 5-Lipoxygenase; Asthma; Biology; Bone Marrow; Bone Marrow Cells; Cell Lineage; Cells; Chronic Myeloid Leukemia; Clinical Trials; Data; Development; Disease; Effectiveness; FDA approved; Foundations; Future; Gene Targeting; Genes; Genetic; Goals; Hematopoietic; Hematopoietic stem cells; Hemorrhagic Thrombocythemia; Human; JAK2 gene; Knockout Mice; Laboratories; Leukocytes; Link; Maintenance; Mediating; Molecular; Molecular Target; Mus; Mutation; Myeloproliferation; Myeloproliferative disease; Nature; Pathway interactions; Patients; Pharmaceutical Preparations; Phase I Clinical Trials; Phenotype; Philadelphia Chromosome; Philadelphia Chromosome Negative Chronic Myelogenous Leukemia; Philadelphia Chromosome Positive Chronic Myelogenous Leukemia; Phosphotransferases; Play; Polycythemia Vera; Population; Primary Myelofibrosis; Publishing; Quality of life; Recording of previous events; Risk; Role; STAT5A gene; Signal Pathway; Signal Transduction; Signaling Molecule; Solid; Stem cells; Symptoms; Testing; Thrombosis; Zileuton; base; bcr-abl Fusion Proteins; beta catenin; human disease; improved; inhibitor/antagonist; kinase inhibitor; leukemia; leukemic stem cell; novel; novel therapeutics; peripheral blood; prevent; self-renewal; stem; stem cell population; treatment strategy

DESCRIPTION (provided by applicant): The JAK2V617F mutation is found in the majority of myeloproliferative neoplasms (MPNs) including polycythemia vera (PV), essential thrombocythemia and primary myelofibrosis. Similar to chromosome- positive (Ph+) chronic myeloid leukemia (CML), these Philadelphia chromosome-negative (Ph-) MPNs are also derived from hematopoietic stem cells (HSCs) and have a risk of developing thrombosis and acute leukemia. There are still no curative therapies for these Ph- MPNs. Recent discovery of the JAK2V617F mutation has promoted the development of targeted therapy using JAK2 inhibitors to inhibit the function of JAK2V617F. Although some early-stage clinical trials show improvement of symptoms and quality of life in patients, the long-term effectiveness of these JAK2 inhibitors remains to be determined. There are already some concerns for the side effects of these drugs. On the other hand, it has been shown that inhibition of JAK2V617F with a JAK2 inhibitor does not eradicate PV-initiating cells, implying that inhibition of the kinase activity o JAK2V617F with a JAK2 inhibitor is unlikely to cure MPNs, which is a situation similar to the treatment of Ph+ CML with BCR-ABL kinase inhibitors that control but do not cure CML. The development of a curative therapy for MPNs requires in-depth studies of the molecular basis of JAK2V617F in initiation and maintenance of these diseases for identifying new and effective target genes. In this application, we focus on PV, a major form of MPNs associated with JAK2V617F. We have observed that Ph+ CML and Ph- MPNs involve the same HSC cell population and have similar myeloproliferative phenotype, suggesting that the disease-initiating cells for CML and PV might share some common regulatory mechanisms. My laboratory has a history of studying the biology and molecular targeting of CML-initiating cells or leukemia stem cells (LSCs) in CML, and we show that the survival and self-renewal of LSCs require the arachidonate 5- lipoxygenase gene (Alox5) and that Alox5 is essential for CML development (Chen et al. Loss of the Alox5 gene impairs leukemia stem cells and prevents chronic myeloid leukemia. Nature Genetics 41:783-792, 2009). We also show that inhibition of Alox5 function leads to eradication of LSCs and prolonged survival of CML mice. Our preliminary data show that JAK2V617F activates Alox5 and loss of the Alox5 gene impedes the development of JAK2V617F-induced PV in mice, which is supported by prolonged survival of PV mice treated with an Alox5 inhibitor. These preliminary results allow us to hypothesize that Alox5 plays a significant role in the development of PV induced by JAK2V617F and is a potential target gene for the treatment of PV. The specific aims are: 1) To determine signaling pathways involved in Alox5 activation by JAK2V617F; and 2) To test whether inhibition of the Alox5 pathway suppresses mouse and human PV cells. These studies will build a solid foundation for future PV clinical trials by targeting the Alox5 pathway. PUBLIC HEALTH RELEVANCE: The JAK2V617F mutation is found in almost all patients with polycythemia vera (PV) that disrupts bone marrow functions and becomes leukemia. JAK2 inhibitors improve symptoms and quality of life but their long-term effectiveness remains to be determined. JAK2 inhibitors do not eradicate PV-initiating cells, and are unlikely to cure the disease. We have observed that JAK2V617F activates a novel gene called Alox5 and loss of this gene impedes the PV development in mice. Also, an Alox5 inhibitor prolongs survival of PV mice. These preliminary results indicate that Alox5 is a promising target gene for PV treatment. Our studies in this application will build a solid foundation for future PV clinical trials by targting the Alox5 pathway.

描述（由申请人提供）：JAK2V617F突变是在大多数骨髓增生性肿瘤（MPN）中发现的，包括多余的Vera（PV），必需的血小板细胞和原发性骨髓纤维纤维化。与染色体阳性（PH+）慢性髓样白血病（CML）相似，这些费城染色体阴性（PH-）MPN也来自造血干细胞（HSC），并具有发展血栓形成和急性白血病的风险。这些pH-MPN仍然没有治疗疗法。 JAK2V617F突变的最新发现促进了使用JAK2抑制剂抑制JAK2V617F功能的靶向治疗的发展。尽管一些早期临床试验表明患者症状和生活质量的改善，但这些JAK2抑制剂的长期有效性仍有待确定。这些药物的副作用已经有一些担忧。另一方面，已经表明，用JAK2抑制剂对JAK2V617F抑制不会消除PV发射细胞，这意味着抑制激酶活性O JAK2V617F用JAK2抑制剂抑制jak2v617f与ph+ cml的治疗方法相似，与ph+ cml相似的情况是不可能治疗的情况。 CML。用于MPN的治疗疗法的开发需要对JAK2V617F的分子基础进行深入研究，以识别这些疾病的启动和维持，以鉴定新的有效的靶基因。在此应用程序中，我们专注于PV，这是与JAK2V617F相关的主要MPN形式。我们已经观察到pH+ CML和pH-MPN涉及相同的HSC细胞群，并且具有相似的骨髓增生性表型，这表明CML和PV的疾病引发细胞可能具有某些常见的调节机制。我的实验室有研究CML启动细胞或白血病干细胞（LSC）的生物学和分子靶向的历史，我们表明，LSC的生存和自我更新需要芳基酮5-脂肪氧合酶基因（Alox5），Alox5对CML的发展是CML的损失。预防慢性髓样白血病。我们还表明，抑制ALOX5功能会导致消除LSC和CML小鼠的延长存活率。我们的初步数据表明，JAK2V617F激活ALOX5和ALOX5基因的丧失阻碍了小鼠JAK2V617F诱导的PV的发展，这得到了用Alox5抑制剂治疗的PV小鼠的长期存活支持。这些初步结果使我们可以假设ALOX5在JAK2V617F引起的PV发展中起着重要作用，并且是治疗PV的潜在靶基因。具体目的是：1）确定JAK2V617F激活ALOX5激活的信号传导途径； 2）测试抑制ALOX5途径是否抑制小鼠和人PV细胞。这些研究将通过针对ALOX5途径来为未来的PV临床试验奠定坚实的基础。 公共卫生相关性：JAK2V617F突变均在几乎所有多余的Vera（PV）患者中发现，破坏了骨髓功能并变为白血病。 JAK2抑制剂改善了症状和生活质量，但其长期效率仍有待确定。 JAK2抑制剂不会根除PV发射细胞，并且不可能治愈该疾病。我们已经观察到JAK2V617F激活了一个名为Alox5的新基因，而该基因的丧失阻碍了小鼠的PV发育。另外，ALOX5抑制剂还延长了PV小鼠的存活。这些初步结果表明ALOX5是PV处理的有希望的靶基因。我们在该应用程序中的研究将通过损害ALOX5途径来为未来的PV临床试验奠定坚实的基础。