Interferon Responses in Myeloid Leukemia

粒细胞白血病中的干扰素反应

基本信息

批准号：
8105113
负责人：
Serge Y Fuchs
金额：
$ 32.2万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-06 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8105113
关键词：
Bcr-Abl tyrosine kinase Cell Line Cells Chronic Myeloid Leukemia Dasatinib Data Disease Dose Down-Regulation Ectopic Expression Effectiveness Endocytosis Frequencies Gatekeeping Gene Expression Generations Genetic Gleevec Human IFNAR1 gene Imatinib Imatinib mesylate In Vitro Interferon-alpha Interferons Life Malignant Neoplasms Mediating Molecular Molecular Cytogenetics Molecular Genetics Molecular Target Mutation Myeloid Leukemia Newly Diagnosed Pathway interactions Patients Phosphorylation Phosphotransferases Play Protein Kinase Protein-Serine-Threonine Kinases RNA Interference Reporting Resistance Role Sampling Signal Transduction Signal Transduction Pathway Stem cells Testing Toxic effect Treatment Efficacy Tyrosine Kinase Inhibitor Ubiquitination base bcr-abl Fusion Proteins cytokine improved in vivo inhibitor/antagonist insight killings kinase inhibitor mouse model mutant novel pre-clinical progenitor public health relevance receptor research clinical testing research study response standard of care stem cell population success tool tumor

项目摘要

DESCRIPTION (provided by applicant): Imatinib mesylate (IM, also termed Gleevec) has replaced interferon alpha (IFNa) as the standard of care for patients with newly diagnosed chronic myeloid leukemia (CML) due to higher response frequency, lesser toxicity and better survival. While rapidly killing differentiated CML cells, IM fails to act against more primitive leukemic stem cells and early progenitors. As a result, patients receiving IM are not cured and require life-long treatment that is often compromised by resistance to IM due to mutations in molecular target of IM - the Bcr-Abl tyrosine kinase. There are indications that in order to achieve curative effect in CML patients, a combination of inhibitors of Bcr-Abl and the leukemic stem cell-targeting agents (such as IFNa) might be required. While a few reports on success in patients receiving both types of therapy provide new enthusiasm for the re-introduction of IFNa into the management of CML, the molecular mechanisms that underlie the rationale for combining Bcr-Abl inhibitors with IFNa remain to be delineated. Our preliminary data demonstrates that Bcr-Abl activity stimulates the phosphorylation-mediated downregulation of IFNAR1 - a protein receptor that is central for all of the effects of IFNa on cells. This downregulation might confer a suppression of cellular responses to IFNa reported in CML cells. We propose a hypothesis that signal transduction pathways induced and sustained by Bcr-Abl impede the responses of CML cells to IFNa via inducing phosphorylation-dependent degradation of IFNAR1. We also hypothesize that accelerated degradation of IFNAR1 induced by Bcr-Abl plays an important role in regulating the sensitivity of CML cells to IM and IFNa. In this application, we propose to test this hypothesis by (i) determining the role of Bcr-Abl-induced downregulation of IFNAR1 in the inhibitory effect of Bcr-Abl on cellular responses of cells to IFNa; (ii) delineating the mechanisms by which BCR-Abl down-regulates IFNAR1 and its signaling; and (iii) assessing the role IFNAR1 stabilization plays in the therapeutic efficacy of IFNa and BCR-Abl inhibitors. We anticipate that these studies will provide significant insight into the mechanisms by which CML cells expressing constitutively active Bcr-Abl promote IFNAR1 degradation, suppress IFNa signaling and evade IFN-induced anti-tumor defenses. We also predict that these studies will identify critical regulators of these responses that can potentially serve as novel and important targets for increasing the efficacy of therapy against CML. Finally, the outlined experiments will provide the pre-clinical evaluation for sequence-specific combining of Bcr-Abl inhibitors with IFNa to optimize the existing regimes for CML management. PUBLIC HEALTH RELEVANCE: Constitutive activity of Bcr-Abl fusion protein kinase causes chronic myeloid leukemia (CML). Inhibitors of Bcr-Abl such as imatinib have replaced the cytokine interferon alpha (IFNa) as the primary treatment for the management of patients with this malignancy. We found that Bcr-Abl signaling might impair cellular responses to IFNa by downregulating its receptor. Here we investigate the relationship between Bcr-Abl activity and IFNa signaling as well as the relationship between the molecular basis of the combination of imatinib and IFNa for CML treatment. These studies will yield results that are important for improving treatment of patients with CML.

描述（由申请人提供）：甲磺酸伊马替尼（IM，也称为格列卫）已取代干扰素α（IFNa）成为新诊断慢性粒细胞白血病（CML）患者的标准治疗方法，因为它具有更高的反应频率、更低的毒性和更好的生存率。 IM 在快速杀死分化的 CML 细胞的同时，无法对抗更原始的白血病干细胞和早期祖细胞。因此，接受 IM 治疗的患者无法治愈，需要终生治疗，但由于 IM 分子靶标（Bcr-Abl 酪氨酸激酶）突变，这种治疗往往会受到 IM 耐药性的影响。有迹象表明，为了在CML患者中取得疗效，可能需要联合使用Bcr-Abl抑制剂和白血病干细胞靶向药物（例如IFNa）。虽然接受这两种治疗的患者取得成功的一些报告为将 IFNa 重新引入 CML 治疗提供了新的热情，但 Bcr-Abl 抑制剂与 IFNa 联合治疗的分子机制仍有待阐明。我们的初步数据表明，Bcr-Abl 活性刺激磷酸化介导的 IFNAR1 下调，IFNAR1 是一种蛋白质受体，对于 IFNa 对细胞的所有作用至关重要。这种下调可能会抑制 CML 细胞对 IFNa 的细胞反应。我们提出一个假设，即 Bcr-Abl 诱导和维持的信号转导途径通过诱导 IFNAR1 的磷酸化依赖性降解来阻碍 CML 细胞对 IFNa 的反应。我们还假设 Bcr-Abl 诱导的 IFNAR1 加速降解在调节 CML 细胞对 IM 和 IFNa 的敏感性中发挥重要作用。在本申请中，我们建议通过以下方式检验这一假设：(i)确定Bcr-Abl诱导的IFNAR1下调在Bcr-Abl对细胞对IFNa的细胞反应的抑制作用中的作用； (ii) 描述 BCR-Abl 下调 IFNAR1 及其信号传导的机制； (iii)评估IFNAR1稳定化在IFNa和BCR-Abl抑制剂的治疗功效中所起的作用。我们预计这些研究将为表达组成型活性 Bcr-Abl 的 CML 细胞促进 IFNAR1 降解、抑制 IFNa 信号传导和逃避 IFN 诱导的抗肿瘤防御的机制提供重要的见解。我们还预测，这些研究将确定这些反应的关键调节因子，这些调节因子有可能成为提高 CML 治疗疗效的新颖且重要的靶点。最后，概述的实验将为 Bcr-Abl 抑制剂与 IFNa 的序列特异性组合提供临床前评估，以优化现有的 CML 治疗方案。公共健康相关性：Bcr-Abl 融合蛋白激酶的组成活性会导致慢性粒细胞白血病 (CML)。 Bcr-Abl 抑制剂（例如伊马替尼）已取代细胞因子干扰素 α (IFNa)，成为治疗这种恶性肿瘤患者的主要治疗方法。我们发现 Bcr-Abl 信号传导可能通过下调 IFNa 受体来损害细胞对 IFNa 的反应。在这里，我们研究了 Bcr-Abl 活性与 IFNa 信号传导之间的关系，以及伊马替尼和 IFNa 联合治疗 CML 的分子基础之间的关系。这些研究将产生对于改善 CML 患者治疗非常重要的结果。