Mechanisms and targeting of inflammatory cytokine-driven expansion and progression in AML

项目摘要/摘要 急性髓系白血病(AML)接受化疗后的5年存活率仍然很低，仅为25%。 那些幸存下来的人将遭受终身后果，主要是由于化疗的并发症和疾病 故态复萌是不可避免的。因此，迫切需要新的、改进的治疗方法来快速消除AML细胞 而且完全是。由于AML是一种由多种突变引起的高度异质性疾病，我们认为 AML病例的一个共同的、有针对性的特征是它们直接或间接地受到细胞因子的影响 在骨髓微环境中分泌。我们的长期目标是确定新的药物靶点，以 有选择地根除可能影响急性髓细胞白血病治疗反应的恶性克隆。我们的近期目标 是全面确定炎症途径促进克隆的分子机制 急性髓系白血病的演变。我们发现炎性细胞因子白介素1β(IL-1β)在多种疾病中升高 一组AML患者，既促进了AML细胞的增殖，同时又阻碍了正常细胞的生长。 阻断急性髓系白血病细胞与IL-1之间的通讯可抑制这些效应并降低其存活率 同时又不影响健康的祖先。因为大多数AML患者的细胞具有不同的基因 亚型的生存依赖于IL-1信号，我们预测很大比例的AML患者 可能会从针对这一途径的药物中受益。然而，IL-1信号的直接靶向可能会影响细胞 在健康细胞中发挥作用。因此，我们的研究重点是确定IL-1介导的分子差异 在急性髓系白血病和健康的祖细胞之间。基因表达分析证实IL-1上调ASF1b和 将AML的Marcks与健康的祖细胞进行比较。ASF1b和Marcks调节细胞增殖，DNA 损害反应和急性髓系白血病的炎症反应。我们的数据显示，基因和药物靶向 ASF1b和Marcks通路抑制AML生长。这些发现提出了一些重要的新的 研究方向。在拟议的项目中，我们将测试ASF1b差异激活的假设 与健康祖细胞相比，急性髓系白血病中IL-1β的表达为白血病细胞提供了竞争优势， 这最终会导致AML的进展。具体地说，我们将确定：(1)体外机制通过 ASF1b和Marcks的哪种IL-1激活促进AML细胞的生长；(2)ASF1b和Marcks的作用 在体内赋予IL-1介导的生长优势和推动AML进展的标志；以及(3) ASF1b和MARCKS作为可用小分子抑制剂治疗AML靶点的有效性。至 为了实现我们的目标，我们建立了各种工具，包括4个新的转基因小鼠模型和访问 TLK和Marcks通过与世界知名领导人的合作抑制。确定潜在的 IL-1支持AML发展的分子机制将为设计新的治疗方法铺平道路 战略。

PROJECT SUMMARY/ABSTRACT Acute myeloid leukemia (AML) continues to have a dismal 5-years survival rate of <25% with chemotherapy. Those who survive suffer lifelong consequences, largely due to complications from chemotherapy, and disease relapse is inevitable. Thus, there is an urgent need for new, improved treatments to eliminate AML cells rapidly and completely. Since AML is a highly heterogeneous disease caused by multiple mutations, we propose that a common, targetable feature among AML cases is that they are directly and indirectly influenced by cytokines secreted in the bone marrow microenvironment. Our long-term goal is to identify novel drug targets to selectively eradicate malignant clones that may impact the response to AML therapies. Our immediate goals are to comprehensively determine the molecular mechanisms by which inflammatory pathways promote clonal evolution in AML. We found that the inflammatory cytokine interleukin-1β (IL-1β), which is elevated in a diverse set of AML patients, both encourages AML cells to multiply and simultaneously impedes normal cell growth. Blocking communication between AML cells and IL-1 inhibits these effects and reduces survival of AML cells while sparing healthy progenitors. Because cells from a majority of AML patients with different genetic subtypes are dependent on IL-1 signaling for their survival, we predict that a large percentage of AML patients might benefit from drugs targeting this pathway. However, direct targeting of IL-1 signaling may impact cellular functions in healthy cells. We therefore focused our study on defining the IL-1-mediated molecular differences between AML and healthy progenitors. Gene expression analysis identified that IL-1 upregulates ASF1B and MARCKS in AML compared to healthy progenitors. ASF1B and MARCKS regulate cell proliferation, DNA damage response, and inflammation in AML. Our data shows that genetic and pharmacological targeting of ASF1B and MARCKS pathways suppresses AML growth. These findings suggest a number of important new research directions. In the proposed project, we will test the hypothesis that differential activation of ASF1B and MARCKS by IL-1β in AML versus healthy progenitors provides a competitive advantage to leukemic cells, which ultimately leads to AML progression. Specifically, we will determine: (1) the in vitro mechanisms by which IL-1 activation of ASF1B and MARCKS promotes the growth of AML cells; (2) the roles of ASF1B and MARCKS in conferring IL-1-mediated growth advantage and driving AML progression in vivo; and (3) the validity of ASF1B and MARCKS as therapeutic targets in AML using available small-molecule inhibitors. To achieve our goals we established a variety of tools including 4 new transgenic mouse models and access to TLK and MARCKS inhibitor through collaborations with world-renowned leaders. Determining the underlying molecular mechanisms by which IL-1 supports AML development will pave the way to designing new treatment strategies.