Interferon Responses in Myeloid Leukemia

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）作为新诊断的慢性粒细胞白血病（CML）患者的标准治疗，因为其反应频率更高，毒性更小，生存率更好。 虽然快速杀死分化的CML细胞，但IM不能对更原始的白血病干细胞和早期祖细胞起作用。因此，接受IM的患者不能治愈，需要终身治疗，这通常会受到IM分子靶点-Bcr-Abl酪氨酸激酶突变引起的IM耐药性的影响。有迹象表明，为了在CML患者中获得疗效，可能需要Bcr-Abl抑制剂和白血病干细胞靶向药物（如IFNa）的组合。虽然一些关于接受两种类型治疗的患者成功的报告为将IFNa重新引入CML管理提供了新的热情，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下调IFNAR 1-一种蛋白质受体，这是所有IFNa对细胞的影响的核心。这种下调可能会抑制CML细胞中报道的对IFNa的细胞应答。我们提出了一个假设，诱导和维持Bcr-Abl的信号转导通路阻碍CML细胞的反应，通过诱导磷酸化依赖的降解IFNAR 1的IFNa。我们还推测Bcr-Abl诱导的IFNAR 1的加速降解在调节CML细胞对IM和IFNa的敏感性中起重要作用。在本申请中，我们建议通过以下方式来检验这一假设：（i）确定Bcr-Abl诱导的IFNAR 1下调在Bcr-Abl对细胞对IFNa的细胞应答的抑制作用中的作用;（ii）描绘BCR-Abl下调IFNAR 1及其信号传导的机制;以及（iii）评估IFNAR 1稳定化在IFNa和BCR-Abl抑制剂的疗效中所起的作用。我们预计，这些研究将提供显着的洞察CML细胞表达组成型活性Bcr-Abl促进IFNAR 1降解，抑制IFNa信号转导和逃避IFN诱导的抗肿瘤防御的机制。我们还预测，这些研究将确定这些反应的关键调节因子，这些调节因子可能成为提高CML治疗疗效的新的重要靶点。最后，概述的实验将提供Bcr-Abl抑制剂与IFNa的序列特异性组合的临床前评价，以优化CML管理的现有方案。 公共卫生相关性：Bcr-Abl融合蛋白激酶的组成性活性导致慢性粒细胞白血病（CML）。Bcr-Abl抑制剂如伊马替尼已取代细胞因子干扰素α（IFNa）作为治疗这种恶性肿瘤患者的主要治疗方法。 我们发现Bcr-Abl信号可能通过下调其受体来损害细胞对IFN α的反应。在这里，我们研究Bcr-Abl活性和IFNa信号之间的关系，以及伊马替尼和IFNa联合治疗CML的分子基础之间的关系。这些研究将产生对改善CML患者治疗的重要结果。

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.