Zileuton as a chemopreventive agent for chronic myeloid leukemia

齐留通作为慢性粒细胞白血病的化学预防剂

基本信息

批准号：
8759045
负责人：
Shaoguang Li
金额：
$ 34.76万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8759045
关键词：
Adult Affect Anti-Inflammatory Agents Anti-inflammatory Apoptosis Arachidonate 5-Lipoxygenase Asthma Biological Assay Bone Marrow Transplantation CD34 gene Cell Culture Techniques Cell Survival Cell physiology Cells Chemopreventive Agent Child Chronic Myeloid Leukemia Colon Data Development Disease Disease remission Engraftment Enzymes Esophagus FDA approved Foundations Gene Targeting Genes Genetic Human Imatinib Immunocompromised Host In Vitro Individual Inflammation Mediators Inflammatory Knockout Mice Leukotriene A4 Leukotriene B4 Leukotriene C4 Leukotriene Production Leukotrienes Liver Lung Malignant Neoplasms Metabolic Modification Molecular Mus Myeloid Leukemia Nature Non obese Oncogenes P-Selectin Pancreas Pathway interactions Patients Pharmaceutical Preparations Prevention Prevention strategy Production Publishing Regulation Regulator Genes Relapse Reporting Residual state Role Signal Transduction Skin Solid Solid Neoplasm Sorting - Cell Movement Stem cells Testing Transcript Up-Regulation Work Zileuton base bcr-abl Fusion Proteins beta catenin carcinogenesis chimeric gene clinically significant diabetic hypoxia inducible factor 1 in vitro testing in vivo kinase inhibitor leukemia leukemic stem cell novel novel strategies peripheral blood prevent public health relevance

项目摘要

DESCRIPTION (provided by applicant): This application aims to develop a novel strategy for preventing chronic myeloid leukemia (CML) by targeting leukemia stem cells (LSCs) that initiate CML. This idea is based on our recently published finding that the arachidonate 5-lipoxygenase (5-LO) gene (Alox5) is a key survival-regulatory gene in LSCs (Chen et al. Nature Genetics 41:783-792, 2009), suggesting that Alox5 serves as a potential target gene for preventing CML. A known function of 5-LO is to produce inflammatory leukotrienes, and enzymatic activity of 5-LO can be inhibited by an FDA-approved human anti-inflammatory drug Zileuton (Zyflo). Thus, Zileuton could be a promising chemopreventive agent for CML; the underlying mechanisms are totally unknown and could be related to the effects of Zileuton on the known metabolic function or novel functions of Alox5 or both. Our preliminary studies also show that Zileuton suppresses human CML stem cells. Because CML is derived from a stem cell harboring the BCR-ABL oncogene, our findings prompt us to hypothesize that Zileuton acts on an Alox5-related molecular network responsible for survival regulation of LSCs and is a potential chemopreventive agent for CML. Testing this hypothesis is of clinical significance and would benefit: 1) individuals who have detectable BCR-ABL transcripts but have not developed CML; 2) CML patients who are in molecular remission and hope or have to stop a BCR-ABL kinase inhibitor; and 3) CML patients who had bone marrow transplantation but may still have residual leukemia cells. Mechanistically, because the known Alox5 function is to produce leukotrienes, Zileuton may prevent CML by reducing their production, which needs to be tested. Our preliminary data also reveal novel functions of Alox5, suggesting that Zileuton may suppress Alox5 function through regulating pathways unrelated to production of leukotrienes. In this regard, our preliminary study in shows that loss of P-selectin causes upregulation of Hif1a which enhances Alox5 expression in LSCs and that Alox5 signals to beta-catenin. Inhibition of LSCs by Zileuton provides a novel preventive strategy for CML. In-depth study of Zileuton function helps to identify more Alox5-related target genes for preventing CML and provides a rationale for modifying existing drugs with activities on Alox5 and related genes. The specific aims are: 1) To determine whether leukotrienes promote the survival of LSCs, whether Zileuton suppresses LSCs through reducing leukotriene production and what the underlying mechanism is; 2) To determine the intracellular pathways affected by Zileuton in LSCs; and 3) To determine whether Zileuton similarly regulates the Alox5 pathway in human CML stem cells and reduces engraftment of human CML cells in immunocompromised mice. Although we focus on CML, Zileuton is also a potential chemopreventive agent for solid tumors as Alox5 is associated with carcinogenesis in the colon, lung, pancreas, liver, esophagus, skin.

描述（由申请人提供）：本申请旨在通过靶向启动CML的白血病干细胞（LSC）来制定一种新的策略，以防止慢性髓样白血病（CML）。这个想法是基于我们最近发表的发现，即蛛网酸5-脂氧合酶（5-lo）基因（Alox5）是LSC中的一个关键生存调节基因（Chen等人自然遗传学41：783-792，2009），表明Alox5可作为预防CML的潜在靶基因。 5-LO的已知功能是产生炎症白细胞，5-LO的酶促活性可以被FDA批准的人类抗炎药Zileuton（Zyflo）抑制。因此，Zileuton可能是CML的有希望的化学预防剂。基本机制是完全未知的，可能与Zileuton对Alox5或两者兼有的新代谢功能或新功能的影响有关。我们的初步研究还表明，Zileuton抑制了人CML干细胞。由于CML源自具有BCR-ABL癌基因的干细胞，因此我们的发现促使我们假设Zileuton作用于负责LSC生存调节的ALOX5相关分子网络，并且是CML的潜在化学剂。检验该假设具有临床意义，将受益：1）具有可检测到的BCR-ABL转录本但未开发CML的个体； 2）处于分子缓解并希望或必须停止BCR-ABL激酶抑制剂的CML患者； 3）患有骨髓移植但仍有残留白血病细胞的CML患者。从机械上讲，由于已知的ALOX5功能是产生白三烯，因此Zileuton可以通过减少其生产来预防CML，需要测试。我们的初步数据还揭示了Alox5的新功能，这表明Zileuton可以通过调节与白细胞生产无关的途径来抑制Alox5功能。在这方面，我们在初步的研究表明，P-选择素的丧失会导致HIF1A上调，从而增强了LSC中的Alox5表达，并且ALOX5信号对β-catenin信号。 Zileuton对LSC的抑制为CML提供了一种新颖的预防策略。对Zileuton功能的深入研究有助于鉴定更多与ALOX5相关的靶基因，以防止CML，并为通过Alox5和相关基因的活性修改现有药物提供了理由。具体目的是：1）确定白细胞是否促进LSC的生存，Zileuton是否通过减少白细胞生产以及基本机制来抑制LSC； 2）确定在LSC中受Zileuton影响的细胞内途径； 3）确定Zileuton是否类似地调节了人CML干细胞中的Alox5途径，并减少了免疫受损小鼠中人类CML细胞的植入。尽管我们专注于CML，但Zileuton也是实体瘤的潜在化学预防剂，因为Alox5与结肠，肺，胰腺，肝脏，肝脏，食道，皮肤的癌变有关。