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/文摘