Interferon Responses in Myeloid Leukemia

粒细胞白血病的干扰素反应

基本信息

批准号：
8448756
负责人：
Serge Y Fuchs
金额：
$ 30.27万
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/8448756
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 leukemic stem cell 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

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 leukemic stem cell 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

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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.

描述（由申请人提供）：伊马替尼梅赛酸盐（IM，也称为Gleevec）已代替了干扰素α（IFNA）作为新诊断的慢性髓样白血病（CML）患者的护理标准，这是由于较高的反应频率，毒性较低，毒性较小，生存率较低。在迅速杀死分化的CML细胞的同时，IM无法对更原始的白血病干细胞和早期祖细胞作用。结果，接受IM的患者未得到治愈，需要终身治疗，这通常因IM的突变IM-BCR-ABL酪氨酸激酶的分子靶标而受到抗药性损害。有迹象表明，为了在CML患者中实现治疗作用，可能需要BCR-ABL的抑制剂和白血病干细胞靶向剂（例如IFNA）的结合。尽管接受两种类型疗法的患者成功的一些报告为将IFNA重新引入CML的管理提供了新的热情，但将BCR-ABL抑制剂与IFNA相结合的基本原理的分子机制仍有待描绘。我们的初步数据表明，BCR-ABL活性刺激了IFNAR1的磷酸化介导的下调 - 一种蛋白受体，这是IFNA对细胞所有作用的核心。这种下调可能会抑制对CML细胞中报告的IFNA的细胞反应。我们提出了一个假设，即通过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的加速降解在调节CML细胞对IM和IFNA的敏感性方面起着重要作用。在此应用中，我们建议通过（i）确定BCR-ABL诱导的IFNAR1下调IFNAR1在BCR-ABL对细胞对IFNA细胞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稳定作用在IFNA和BCR-ABL抑制剂的治疗疗效中发挥作用。我们预计，这些研究将对表达组成型活性BCR-ABL促进IFNAR1降解的CML细胞的机制有很大的见解，抑制IFNA信号传导并逃避IFN诱导的抗肿瘤防御措施。我们还预测，这些研究将确定这些反应的关键调节因子，这些调节可能会成为增加对CML治疗疗效的新颖和重要靶标。最后，概述的实验将提供临床前评估，以针对BCR-ABL抑制剂与IFNA的序列特异性组合，以优化现有的CML管理状态。