Identification of New Targets and Novel Treatment Strategies for Chronic Mye

确定慢性髓性白血病的新靶点和新治疗策略

• 批准号: 8000085
• 负责人: RALPH BERNARD ARLINGHAUS
• 金额: $ 17.75万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8000085
• 关键词: 1-Phosphatidylinositol 3-Kinase; Accelerated Phase; Apoptosis; Binding; Blast Phase; Bone Marrow; Cell Line; Cells; Chronic; Chronic Myeloid Leukemia; Clinical Trials; Complex; Dasatinib; Disease Progression; Doctor of Philosophy; Drug resistance; Gleevec; Goals; Grant; Hematopoietic; Hematopoietic stem cells; Homologous Gene; Human; Imatinib; In Vitro; Induction of Apoptosis; Instruction; Knockout Mice; Laboratories; Lead; Mediating; Medical; Modeling; Molecular; Mus; Mutation; Oncogene Proteins; Oncogenes; Oncogenic; Outcome Study; Patients; Phosphotransferases; Play; Protein Tyrosine Kinase; Protein-Serine-Threonine Kinases; Proteins; Publishing; Regimen; Research; Resistance; Role; STAT3 gene; STAT5A gene; Signal Pathway; Signal Transduction; Staging; System; Therapeutic; Transplantation; United States National Institutes of Health; Work; base; bcr-abl Fusion Proteins; inhibitor/antagonist; interest; leukemia; lipocalin 1; mouse model; novel; treatment strategy

PROJECT SUMMARY (See instructions): Idenfificafion of new targets and novel treatment strategies for chronic mvelold leukemia. Ralph B. Arilnahaus. Ph.D.- My laboratory has published new information on several key proteins in chronic myelogenous leukemia that are regulated by the Bcr-Abl oncoprotein. These proteins are lipocalin 2 (NGAL/24p3), Jak2 and Bcr. We were first to discover the role of lipocalin 2 in Bcr-Abl induced leukemia (Lin et al. Oncogene 2005). Our recent studies with 24p3 null mice showed that 24p3 secretion by Bcr-Abl+ cells is a requirement for leukemia inducfion by Bcr-Abl in a mouse model (Leng et al.. Oncogene 2008). Regarding Jak2, we show that it is part of a large signaling network (Samanta et al., Can Res., 2006). Inhibifion of Jak2 induces apoptosis in imatinib-sensitive/resistant Bcr-Abl + cells, in CML cell lines and in cells from blast crisis CML patients. Concerning Bcr, wild-type Bcr protein inhibits the oncogenic function of Bcr-Abl but serine/threonine kinase-defective Bcr enhances the oncogenic effects of Bcr-Abl (Perazzona et al.. Oncogene, 2008). Aim #1, Develop a monoclonal anfibody that blocks lipocalin 2 (NGAL/24p3) activities induced by Bcr-Abl, and investigate the effects in mouse leukemia models. Our goal is to interfere with NGAL function for treatment of CML in combination with other therapeutic regimens such as Gleevec therapy. Aim #2, Investigate the mechanistic effects of new Jak2 inhibitors in imatinib-sensitive and resistant CML cell lines, patient cells, and in patient cells from advanced stages of CML with the long-term goal of doing clinical trials in imafinib-resistant CML and late stage CML (with Dr. Cortes). We hypothesize that a potent Jak2 inhibitor will be useful in the treatment of drug-resistant CML as well as in all stages of CML because of the dominant role of Jak2 in oncogenic signaling in CML cells. We have identified a new Jak2 inhibitor (WP1193) that disrupts the Bcr-Abl/Jak2/HSP90 signaling network complex leading to apoptosis of drug-resistant CML cells and blast crisis CML cells. Surprisingly, preliminary results indicate that the Jak2 kinase phosphorylates Tyr 177 of Bcr-Abl, which upon Jak2 inhibifion drasfically reduced Grb2 binding to the network complex and caused the disruption of the Ras and PI-3 kinase signaling pathways. Importantly, Jak2 inhibition also drastically reduced Bcr-Abl protein levels, causing down-regulafion of STAT5 and STAT3 signaling. Thus, Jak2 inhibition disrupts many If not all oncogenic effects in CML. Aim #3, Invesfigate the role ofthe Bcr Ser/Thr kinase in regulafing Bcr-Abl oncogenic activity. We will search for mutations in the Bcr kinase domain, as we hypothesize that such mutations play a role in CML disease progression.

项目总结（见说明）： 慢性粒细胞白血病新靶点和新治疗策略的确定。拉尔夫B。 阿里纳豪斯博士学位-我的实验室发表了关于慢性炎症中几种关键蛋白质的新信息。 Bcr-Abl癌蛋白调控的骨髓性白血病。这些蛋白质是脂质运载蛋白2 (NGAL/24 p3）、Jak 2和Bcr.我们首先发现了脂质运载蛋白2在Bcr-Abl诱导的白血病中的作用（Lin 等人Oncogene 2005）。我们最近对24 p3缺失小鼠的研究表明，Bcr-Abl+细胞分泌24 p3 是在小鼠模型中通过Bcr-Abl诱导白血病所必需的（Leng et al. Oncogene 2008）。 关于Jak 2，我们表明它是大型信令网络的一部分（Samanta等人，坎水库，2006年）。 抑制Jak 2可诱导伊马替尼敏感/耐药Bcr-Abl +细胞、CML细胞系和AML细胞凋亡。 白血病急变期患者的细胞。关于Bcr，野生型Bcr蛋白可抑制 Bcr-Abl但丝氨酸/苏氨酸激酶缺陷型Bcr增强了Bcr-Abl的致癌作用（Perazzona et al.. Oncogene，2008）。目的#1，开发阻断脂质运载蛋白2（NGAL/24 p3）活性的单克隆抗体 Bcr-Abl诱导的小鼠白血病模型中观察其作用。我们的目标是干扰 NGAL与其他治疗方案如格列卫联合治疗CML的作用 疗法目的#2，研究新型Jak 2抑制剂在伊马替尼敏感和耐药患者中的机制作用 CML细胞系、患者细胞和来自CML晚期的患者细胞，其长期目标是 与科尔特斯博士一起在伊马非尼耐药CML和晚期CML中进行临床试验。我们假设 有效的Jak 2抑制剂将可用于治疗耐药CML以及CML的所有阶段 这是因为Jak 2在CML细胞的致癌信号传导中起主导作用。我们发现了一个新的Jak 2 抑制剂（WP 1193）破坏Bcr-Abl/Jak 2/HSP 90信号网络复合物，导致细胞凋亡 耐药CML细胞和急变CML细胞。令人惊讶的是，初步结果表明，Jak 2 激酶磷酸化Bcr-Abl的Tyr 177，其在Jak 2抑制draslatin后减少Grb 2与 网络复合物，并导致Ras和PI-3激酶信号通路的中断。重要的是， Jak 2抑制也显著降低Bcr-Abl蛋白水平，导致STAT 5和STAT 3下调 发信号。因此，Jak 2抑制破坏了CML中的许多（如果不是全部）致癌作用。目标#3，调查 Bcr Ser/Thr激酶在调节Bcr-Abl致癌活性中的作用我们将寻找基因突变， Bcr激酶结构域，因为我们假设这样的突变在CML疾病进展中发挥作用。