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

AML 中炎症细胞因子驱动的扩张和进展的机制和靶向

• 批准号: 10364734
• 负责人: Anupriya Agarwal
• 金额: $ 11.38万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10364734
• 关键词: ASF1B gene; Acute Myelocytic Leukemia; Address; Automobile Driving; Biochemical; Biological Assay; Biology; Bone Marrow; Bone Marrow Transplantation; Cell Cycle Progression; Cell Proliferation; Cell physiology; Cells; Characteristics; Clonal Evolution; Collaborations; Communication; Critical Pathways; Cues; DNA Damage; Data; Development; Disease; Disease Progression; Drug Targeting; Drug resistance; Ectopic Expression; FLT3 gene; Gene Expression Profiling; Genes; Genetic; Genetic Heterogeneity; Goals; Growth; Impairment; In Vitro; Inflammation; Inflammatory; Interleukin-1; Interleukin-1 beta; Investigation; Knockout Mice; Leukemic Cell; MARCKS gene; Malignant - descriptor; Mediating; Mediator of activation protein; Modeling; Molecular; Mus; Mutation; Non-Malignant; Normal Cell; Pathway interactions; Patients; Pharmacology; Phosphorylation; Phosphotransferases; Process; Recurrent disease; Reporting; Research; Role; Sampling; Signal Transduction; Survival Rate; Testing; Transgenic Mice; Up-Regulation; Xenograft Model; acute myeloid leukemia cell; base; cancer cell; cell growth; chemotherapy; cytokine; design; differential expression; disease heterogeneity; effective therapy; gain of function; immune function; improved; in vivo; inhibitor; insight; knock-down; leukemogenesis; mouse model; new therapeutic target; novel; novel therapeutics; pre-clinical; progenitor; programs; receptor expression; replication stress; response; side effect; small molecule; small molecule inhibitor; targeted agent; targeted treatment; therapeutic target; tool; transcriptome sequencing; transplant model; treatment strategy

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.

项目总结/摘要 急性髓性白血病（AML）化疗的5年生存率仍然很低，<25%。 那些幸存下来的人遭受终身的后果，主要是由于化疗和疾病的并发症 复发是不可避免的。因此，迫切需要新的改进的治疗方法来快速消除AML细胞。 彻底地由于AML是由多种突变引起的高度异质性疾病，我们提出， AML病例的一个共同的、可靶向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， 选择性根除可能影响AML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形成的分子机制， AML的演变我们发现，炎症细胞因子白细胞介素-1 β（IL-1β）在不同的 一组AML患者，既鼓励AML细胞增殖，同时又阻碍正常细胞生长。 阻断AML细胞和IL-1 β之间的通讯可抑制这些作用并降低AML细胞的存活率 而不伤害健康的祖先因为来自大多数AML患者的细胞具有不同的遗传学特征， 亚型的生存依赖于IL-1信号传导，我们预测大部分AML患者 可能受益于针对这一途径的药物。然而，直接靶向IL-1信号传导可能会影响细胞内的 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， AML和健康祖细胞之间的关系基因表达分析表明IL-1上调ASF 1B， 与健康祖细胞相比，AML中的MARCKS。ASF 1B和MARCKS调节细胞增殖，DNA 损伤反应和炎症。我们的数据表明，遗传和药理学靶向的 ASF 1B和MARCKS通路抑制AML生长。这些发现表明了一些重要的新的 研究方向。在这个项目中，我们将测试ASF 1B的差异激活的假设， 并且AML中IL-1β的MARCKS相对于健康祖细胞提供了对白血病细胞的竞争优势， 最终导致AML进展。具体而言，我们将确定：（1）体外机制， 其中IL-1激活ASF 1B和MARCKS促进AML细胞的生长;（2）ASF 1B和MARCKS的作用 MARCKS在体内赋予IL-1介导的生长优势和驱动AML进展中的作用;和（3）MARCKS在体内赋予IL-1介导的生长优势和驱动AML进展中的作用。 ASF 1B和MARCKS作为AML治疗靶点的有效性使用可用的小分子抑制剂。到 为了实现我们的目标，我们建立了各种工具，包括4种新的转基因小鼠模型， TLK和MARCKS抑制剂通过与世界知名的领导者合作。确定基础 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 战略布局