Differentiation-Dependent Targeting of Glycosylated Polyketides in Clonal Hematopoietic Disorders

克隆性造血疾病中糖基化聚酮化合物的分化依赖性靶向

• 批准号: 10053330
• 负责人: Benjamin Reisman
• 金额: $ 4.03万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-01 至 2022-04-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10053330
• 关键词: AML/MDS; Acute Myelocytic Leukemia; Affect; Affinity; Affinity Chromatography; Azides; Bacteria; Biological; Biological Assay; Biological Models; Blood Cells; Cancerous; Cells; Chemicals; Clinical; Coupled; Cytometry; Development; Disease; Dysmyelopoietic Syndromes; Environment; Exhibits; Family; Flow Cytometry; Foundations; Goals; Hand; Hematologic Neoplasms; Hematological Disease; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Human; Human body; Individual; Lead; Macrolides; Malignant - descriptor; Maps; Mature Lymphocyte; Mentorship; Molecular; Molecular Target; Myeloid Cells; Myeloid Leukemia; Natural Products; Nature; Pathway interactions; Patients; Phase; Phenotype; Physicians; Polyenes; Population; Process; Production; Proteomics; Recurrence; Reporting; Resolution; Role; Route; Sampling; Scientist; Soil; Therapeutic Uses; Training; Treatment Failure; analog; apoptolidin; apoptosis in lymphocytes; base; bioactive natural products; biological systems; cell type; cytotoxic; cytotoxicity; drug discovery; hematopoietic differentiation; hematopoietic hierarchy; leukemia; leukemic stem cell; metabolomics; microbial; myeloid leukemia cell; premalignant; protein purification; small molecule; small molecule therapeutics

Project Summary / Abstract Small molecules form the foundation of our toolbox of clinically used therapeutics as well as chemical probes for studying biological systems. However, their applications can be complicated by a lack of cell-type selectivity for the cell subsets responsible for disease. This is particularly true of compounds used to treat hematologic cancers, most of which are natural product derivatives that target rapidly dividing cells – including both cancerous cells and healthy hematopoietic cells, which in healthy individuals generate 3x1011 new blood cells each day. An additional limitation of this approach is that antiproliferative therapies fail to eliminate the relatively quiescent leukemic stem cells (LSCs), which survive therapy and often lead to recurrence. Our group recently discovered that two families of glycosylated polyketides compounds produced by the soil bacteria Nocardiopsis FU-40 exhibit striking selectivity for distinct subsets of cells found in patients with acute myeloid leukemia (AML). The ciromicins appears to be selectively cytotoxic towards immature myeloid leukemia cells and leukemic stem cells, while the apoptolidins selectively target mature lymphocytes. We hypothesize that this represents selective targeting of hematopoietic cells at defined stages of maturation – differentiation dependent targeting. The proposed project will assess the relative cell-type selectivity of these compounds in normal and abnormal hematopoiesis and attempt to define the molecular basis of their observed selectivity. In Aim 1, we will investigate the extent to which the ciromicins and apoptolidins selectively target developmentally defined hematopoietic cell subsets. With the help of our collaborators, we will use mass-cytometry to comprehensively characterize the hematopoietic hierarchy in healthy hematopoiesis, myelodysplastic syndrome (MDS), and acute myeloid leukemia (AML), and how it is perturbed by treatment with the ciromicins and apoptolidins. In Aim 2, we will attempt to identify the target(s) of the ciromicins and apoptolidins using affinity purification coupled to quantitative proteomics. This approach has the potential to reconcile the observed selectivity of the apoptolidins with their reported mechanism which remains an open question in the field, and will provide the first in depth study of the mechanism of action of the ciromicins. As the phenotype induced by these compounds suggests that they are capable of selectively targeting the subsets of cells responsible for disease, this study may define new targets for understanding and treating clonal hematopoietic disorders. Together, these aims will provide a comprehensive understanding of the mechanism of action of glycosylated polyketides at both single cell and molecular resolution, while simultaneously providing an ideal training and mentorship environment for my development as a physician-scientist.

项目摘要 /摘要 小分子构成了我们的临床使用疗法工具箱以及化学的基础 研究生物系统的问题。但是，由于缺乏细胞类型，它们的应用可能会变得复杂 负责疾病的细胞子集的选择性。用于治疗的化合物尤其如此 血液学癌症，大多数是靶向迅速分裂细胞的天然产物衍生物 - 包括 取消细胞和健康造血细胞，在健康个体中产生3x1011新血液 每天细胞。这种方法的另一个限制是，抗叶替疗法无法消除 相关静止的白血病干细胞（LSC），该干细胞在疗法中生存并经常导致复发。我们的小组 最近发现，土壤细菌产生的两个糖基化聚酮化合物家族 Nocardiopsis Fu-40对急性髓样患者发现的不同细胞子集表现出打击的选择性 白血病（AML）。 ciromicin似乎对未成熟髓样白血病细胞有选择性地细胞毒性 和白血病干细胞，而凋亡蛋白有选择地靶向成熟的淋巴细胞。我们假设这是 代表在确定的成熟阶段选择性靶向造血细胞 - 依赖分化 定位。拟议的项目将评估这些化合物在正常和 造血异常，并试图定义其观察到的选择性的分子基础。在AIM 1中，我们将 研究ciromicins和apoptolidins有选择地靶向开发的定义的程度 造血细胞子集。在我们的合作者的帮助下，我们将使用质量仪表仪全面 表征健康造血症中的造血等级，骨髓增生综合征（MDS）和急性 髓样白血病（AML），以及如何通过用ciromicins和popoptolidins治疗它。在AIM 2中，我们 将尝试使用亲和力纯化结合到 定量蛋白质组学。这种方法有可能调和观察到的apoptolidins的选择性 凭借其报告的机制，这仍然是该领域的一个悬而未决的问题，并将提供第一个深度 研究ciromicins的作用机理。正如这些化合物所诱导的表型所表明的那样 他们能够选择性地靶向负责疾病的细胞子集，本研究可能定义 理解和治疗克隆造血疾病的新目标。这些目标在一起将提供 对单细胞和 分子分辨率，同时为我的理想培训和心态环境提供 作为身体科学家的发展。