Defining the stromal landscape that sustains AML drug resistance

定义维持 AML 耐药性的基质景观

• 批准号: 9756124
• 负责人: Sunil Kumar Joshi
• 金额: $ 5万
• 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: 2019-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9756124
• 关键词: Acute Myelocytic Leukemia; Address; Adhesions; Architecture; Biological; Biological Markers; Bone Marrow; CX3CL1 gene; Cell Surface Receptors; Cells; Clinical; Clinical Trials; Computational algorithm; Data; Development; Diagnosis; Disease; Disease Outcome; Drug resistance; Evaluation; FGF2 gene; Foundations; Genes; Goals; Hematologic Neoplasms; Heterogeneity; Image; Immunofluorescence Immunologic; In Situ; Individual; Institutional Review Boards; Leukemic Cell; Ligands; Location; Malignant Neoplasms; Malignant Stromal Cell; Marrow; Masks; Mediating; Mesenchymal; Molecular; NOTCH3 gene; NTRK2 gene; Nature; Pathologic; Patient-Focused Outcomes; Patients; Process; Proteins; Publishing; Relapse; Resistance; Resistance development; Sampling; Signal Transduction; Stains; Stromal Cells; Surface; Testing; Therapeutic; Time; Transcript; United States; Up-Regulation; Work; acute myeloid leukemia cell; base; cancer cell; chemotherapy; differential expression; drug development; experimental study; improved; inhibitor/antagonist; insight; kinase inhibitor; leukemia; mesenchymal stromal cell; new therapeutic target; novel; resistance mechanism; single-cell RNA sequencing; small molecule; targeted treatment; therapeutic target; therapy resistant; transcriptome sequencing; tumor microenvironment

PROJECT SUMMARY: Acute Myeloid Leukemia (AML) remains a highly fatal disease due to the development of drug resistance during chemotherapy. The tumor microenvironment, in particular the crosstalk between leukemia cells and bone marrow mesenchymal stromal cells, has been implicated to be critical for both cancer development and drug resistance. We recently identified a large number of differentially regulated genes in bulk RNA-sequencing of healthy and AML stroma that potentially support the survival of leukemic cells within the bone marrow microenvironment. However, it is unknown if these transcripts are universally up-regulated in stromal cells or if certain pre-existing subpopulations expand and predominate in the marrow microenvironment to support the survival of leukemia cells. A corollary of this is that evaluation of bulk stromal cells by itself is insufficient to fully explain the process and mechanism by which stromal cells mediate AML drug resistance. As such, the overarching goal of this project is to define the pathological stromal landscape that drives AML drug resistance. I will test the underlying hypothesis that specific mesenchymal stromal cell subpopulations within the microenvironment contribute to drug resistance and enable survival of AML cells throughout the course of therapy. This hypothesis will be tested by performing single-cell RNA-sequencing on AML stroma from patients (1) before treatment, (2) on-treatment, and (3) following the development of drug resistance. Imaging and mechanistic studies will also be performed to spatially localize prioritized subpopulations and investigate the molecular mechanisms that confer drug resistance over time. These data will enable me to identify specific stromal subsets that are dynamically regulated during the development of resistance and change spatially with respect to the location of leukemic cells within the microenvironment. Moreover, these data will provide insight into how these subpopulations alter the AML microenvironment, leading to protection of leukemia cells and, thereby AML relapse. The specific aims of this proposal are as follows: (1) Define specific subsets of mesenchymal stromal cells that correlate with the development of AML drug resistance, and (2) Determine the mechanism by which proteins expressed by stromal cells confer drug resistance within the AML microenvironment. Results from this proposal have the potential to create a paradigm shift in the treatment of AML, emphasizing the need to consider extrinsic mechanisms of resistance that are equally critical in understanding clinical resistance and determining disease outcomes.

项目总结： 急性髓系白血病(AML)仍然是一种高度致命的疾病，因为在 化疗。肿瘤微环境，特别是白血病细胞与骨髓之间的串扰 间充质基质细胞，已被认为是癌症发展和耐药的关键。 我们最近在健康人和健康人的批量RNA测序中发现了大量差异调控基因 AML基质可能支持白血病细胞在骨髓微环境中的生存。 然而，目前尚不清楚这些转录本在基质细胞中是否普遍上调，或者是否某些预先存在 亚群在骨髓微环境中扩大并占优势，以支持白血病的生存 细胞。由此得出的结论是，对大量基质细胞本身的评估不足以完全解释这一过程。 以及基质细胞介导AML耐药的机制。 因此，这个项目的首要目标是定义驱动AML药物的病理间质景观 抵抗。我将测试潜在的假设，即特定的间充质基质细胞亚群 微环境有助于耐药，并使AML细胞在整个过程中存活 心理治疗。这一假设将通过对患者的AML间质进行单细胞RNA测序来验证 (1)治疗前；(2)治疗中；(3)耐药后。成像和 还将进行机械性研究，以在空间上定位按优先顺序排列的亚群，并调查 随着时间的推移产生抗药性的分子机制。这些数据将使我能够确定具体的 在抗性发展过程中动态调节的基质亚群，并在空间上随 关于白血病细胞在微环境中的位置。此外，这些数据将提供洞察力 这些亚群如何改变急性髓系白血病微环境，从而保护白血病细胞， 从而急性髓系白血病复发。 这项建议的具体目标如下：(1)定义特定的间充质基质细胞亚群， 与AML耐药性的发展相关，以及(2)决定蛋白质 基质细胞的表达在急性髓系白血病微环境中产生耐药性。这项提案的结果 有可能在急性髓细胞白血病的治疗中创造范式转变，强调需要考虑外在因素 对了解临床耐药和确定疾病同样重要的耐药机制 结果。