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.

项目概要/摘要 小分子构成了我们临床使用的治疗方法和化学工具箱的基础 然而，由于缺乏细胞类型，它们的应用可能会变得复杂。 对导致疾病的细胞亚群的选择性对于用于治疗的化合物尤其如此。 血液癌症，其中大多数是针对快速分裂细胞的天然产物衍生物 - 包括 癌细胞和健康造血细胞，在健康个体中产生 3x1011 新血液 这种方法的另一个局限性是抗增殖疗法无法消除细胞。 相对静止的白血病干细胞（LSC）在治疗后存活并经常导致复发。 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 对急性髓系患者中发现的不同细胞亚群表现出惊人的选择性 白血病（AML）。西罗霉素似乎对未成熟的骨髓性白血病细胞具有选择性细胞毒性。 和白血病干细胞，而凋亡素选择性地靶向成熟淋巴细胞。 代表在特定的成熟阶段选择性靶向造血细胞 - 分化依赖 拟议的项目将评估这些化合物在正常和正常化合物中的相对细胞类型选择性。 在目标 1 中，我们将研究造血异常并尝试定义其观察到的选择性的分子基础。 研究西罗霉素和凋亡素选择性靶向发育定义的程度 在我们合作者的帮助下，我们将使用质谱细胞术来全面分析造血细胞亚群。 描述健康造血、骨髓增生异常综合征 (MDS) 和急性造血的造血层次结构 髓系白血病 (AML)，以及西罗霉素和凋亡素治疗对其产生的干扰如何在目标 2 中进行。 将尝试使用亲和纯化偶联来鉴定西罗霉素和凋亡素的靶标 这种方法有可能协调观察到的凋亡素的选择性。 他们报告的机制仍然是该领域的一个悬而未决的问题，并将提供第一个深入的 正如这些化合物诱导的表型所示，研究了西罗霉素的作用机制。 他们能够选择性地靶向导致疾病的细胞亚群，这项研究可能会定义 这些目标共同将为理解和治疗克隆性造血疾病提供新的目标。 全面了解糖基化聚酮化合物在单细胞和细胞中的作用机制 分子分辨率，同时为我提供理想的培训和指导环境 作为一名医师科学家的发展。