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

基本信息

批准号：
10588163
负责人：
Anupriya Agarwal
金额：
$ 28.58万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10588163
关键词：
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 Modeling Molecular Mus Mutation Non-Malignant Normal Cell Pathway interactions Patients Phosphorylation Phosphotransferases Process Proliferating Recurrent disease Reporting Research Role Sampling Signal Transduction Survival Rate Testing Transgenic Mice Up-Regulation Xenograft Model acute myeloid leukemia cell 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 leukemia treatment leukemogenesis loss of function mouse model new therapeutic target novel novel therapeutic intervention novel therapeutics pharmacologic 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

项目摘要

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.

项目摘要/摘要急性髓细胞性白血病（AML）的5年生存率在化学疗法中的生存率<25％。那些生存的人终生后果，主要是由于化学疗法的并发症和疾病的并发症复发是不可避免的。这是迫切需要新的，改进的治疗方法来迅速消除AML细胞完全。由于AML是由多个突变引起的高度异质疾病，我们建议 AML案例中的一个常见，有针对性的特征是它们直接和间接受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目标有选择性的放射性恶性克隆可能会影响对AML疗法的反应。我们的直接目标要全面确定炎症途径促进克隆的分子机制 AML的进化。我们发现炎性细胞因子白介素1β（IL-1β），在潜水员中升高一组AML患者都鼓励AML细胞繁殖并只是阻碍正常的细胞生长。阻止AML细胞与IL-1之间的通信抑制这些作用并降低AML细胞的存活率同时保留健康的祖细胞。因为大多数AML患者的细胞不同亚型取决于其生存的IL-1信号传导，我们预测AML患者很大一部分针对这种途径的药物可能会受益。但是，直接靶向IL-1信号可能会影响细胞在健康细胞中起作用。因此，我们将研究重点放在定义IL-1介导的分子差异上在AML和健康祖细胞之间。基因表达分析确定IL-1上调ASF1B和与健康的祖细胞相比，AML中的马克克斯。 ASF1B和Marcks调节细胞增殖，DNA 损伤反应和AML的炎症。我们的数据表明，遗传和药物靶向 ASF1B和MARCKS途径抑制了AML的生长。这些发现表明了许多重要的新研究方向。在拟议的项目中，我们将检验以下假设：ASF1B的差异激活 IL-1β在AML与健康祖细胞中的Marcks为白血病细胞提供了竞争优势，最终导致AML进展。具体而言，我们将确定：（1）通过 ASF1B和MARCK的IL-1激活促进了AML细胞的生长；（2）ASF1B和 Marcks在会议上IL-1介导的生长优势，并在体内推动AML进展；（3） ASF1B和MARCK作为AML中的ASF1B和MARCK的有效性，使用可用的小分子抑制剂。到实现我们的目标，我们建立了各种工具，包括4种新的转基因鼠标模型，并访问 TLK和MARCKS抑制剂通过与世界知名的领导人的合作。确定基础 IL-1支持AML开发的分子机制将为设计新处理铺平道路策略。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Clonal hematopoiesis related TET2 loss-of-function impedes IL1β-mediated epigenetic reprogramming in hematopoietic stem and progenitor cells.

DOI：
10.1038/s41467-023-43697-y
发表时间：
2023-12-07
期刊：
NATURE COMMUNICATIONS
影响因子：
16.6
作者：
McClatchy, J.;Strogantsev, R.;Wolfe, E.;Lin, H. Y.;Mohammadhosseini, M.;Davis, B. A.;Eden, C.;Goldman, D.;Fleming, W. H.;Conley, P.;Wu, G.;Cimmino, L.;Mohammed, H.;Agarwal, A.
通讯作者：
Agarwal, A.