Role of PGDH in leukemia pathogenesis

PGD​​H 在白血病发病机制中的作用

• 批准号: 8373391
• 负责人: MICHAEL L CLEARY
• 金额: $ 33.28万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-10 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8373391
• 关键词: Acute leukemia; Address; Affect; Biochemical; Bioinformatics; Biological Assay; Biological Markers; Biological Models; Blood Cells; Cell Line; Cell Maintenance; Cell physiology; Cells; Data; Enzymes; Etiology; Genetic; Goals; Hematopoiesis; Hematopoietic Neoplasms; Hematopoietic stem cells; Human; Hydroxyprostaglandin Dehydrogenases; In Vitro; Knockout Mice; Link; Malignant Neoplasms; Mediator of activation protein; Metabolic; Metabolism; Molecular; Molecular Profiling; Mus; Oncogenic; Pathogenesis; Pathway interactions; Process; Property; Prostaglandins; Proteins; Regulation; Role; Signal Transduction; Stem cells; Structure; Techniques; base; cancer stem cell; defined contribution; gain of function; in vivo; insight; leukemia; leukemic stem cell; leukemogenesis; mouse model; neoplastic; novel; progenitor; self-renewal; therapeutic target

DESCRIPTION (provided by applicant): The overall objectives of the studies proposed in this application are to investigate the molecular pathways that sustain leukemia stem cells with the ultimate goal of defining novel cancer biomarkers and therapeutic targets. The proposed studies build on our recent discoveries that PGDH (NAD+-dependent 15-hydroxyprostaglandin dehydrogenase), a key enzyme involved in metabolic inactivation of prostaglandins, is implicated in the pathogenesis of a major subset of acute leukemia. It is highly expressed in leukemia stem cells, and serves as a crucial mediator in the MLL/HOX pathway that regulates leukemia stem cell self-renewal. The implicated role of PGDH is highly unexpected, as it has not previously been associated with contributing to cancer causation, which contrasts with earlier proposed protective roles. Even more unexpected, is our observation that the contributions of PGDH to leukemia pathogenesis are independent of its enzymatic activity, thus inferring that PGDH has a previously unknown non-canonical and novel biochemical function. We hypothesize that PGDH qualitatively regulates self-renewal to induce aberrant stem cell and/or progenitor expansion, a hypothesis that will be addressed in three specific aims. In Specific Aim #1, we will determine the mechanism for the non-canonical role of PGDH in leukemia pathogenesis. Using gain-of-function genetic approaches in mouse model systems, we will perform structure/function studies to identify leukemia-specific functional domains of PGDH. This will direct subsequent biochemical studies to identify proteins that specifically associate with essential domains required for PGDH oncogenic contributions. Studies in Specific Aim #2 will define the molecular pathways sustained by PGDH in leukemia stem cells using a combination of mouse models of acute leukemia as well as human leukemia cell lines and cells. The molecular pathways affected by PGDH will be characterized using high throughput expression profiling techniques, in conjunction with high-end bioinformatics to establish its role in human leukemia subtypes. In Specific Aim #3 we will define the role of PGDH in normal hematopoiesis using a genetic approach with a particular emphasis on hematopoietic stem cell maintenance and self-renewal in PGDH conditional knockout mice. A greater understanding of the non-canonical functions of PGDH in cancer versus normal stem cells will provide a unique biomarker and facilitate efforts to achieve more efficacious therapies by selectively targeting leukemia stem cells while sparing hematopoietic stem cells. PUBLIC HEALTH RELEVANCE: The studies in this application investigate a key molecular pathway that sustains leukemia stem cells, the crucial cell subpopulation responsible for maintaining cancers of the blood-forming cells. Particular emphasis will focus on a novel role in cancer stem cell function for an enzyme otherwise associated with prostaglandin metabolism, and not previously implicated in cancer causation. A greater understanding of the unique functions for this factor in cancer versus normal stem cells will facilitate efforts to selectively target cancers to achieve more efficacious therapies.

描述（由申请人提供）：本申请中提出的研究的总体目标是研究维持白血病干细胞的分子途径，最终目标是定义新的癌症生物标志物和治疗靶点。拟议的研究建立在我们最近的发现之上，即 PGDH（NAD+ 依赖性 15-羟基前列腺素脱氢酶）是参与前列腺素代谢失活的关键酶，与急性白血病主要亚型的发病机制有关。它在白血病干细胞中高表达，并作为 MLL/HOX 通路中调节白血病干细胞自我更新的关键介质。 PGD​​H 所涉及的作用是非常出乎意料的，因为它以前并未被认为与癌症的发生有关，这与之前提出的保护作用形成鲜明对比。更出乎意料的是，我们观察到PGDH对白血病发病机制的贡献与其酶活性无关，从而推断PGDH具有以前未知的非规范和新颖的生化功能。我们假设 PGDH 定性地调节自我更新以诱导异常干细胞和/或祖细胞扩增，这一假设将在三个具体目标中得到解决。在具体目标#1 中，我们将确定 PGDH 在白血病发病机制中的非典型作用机制。在小鼠模型系统中使用功能获得性遗传方法，我们将进行结构/功能研究，以确定 PGDH 的白血病特异性功能域。这将指导后续的生化研究，以确定与 PGDH 致癌贡献所需的重要结构域特异性相关的蛋白质。具体目标#2 的研究将结合急性白血病小鼠模型以及人类白血病细胞系和细胞，确定白血病干细胞中 PGDH 维持的分子途径。将使用高通量表达谱技术结合高端生物信息学来表征受 PGDH 影响的分子途径，以确定其在人类白血病亚型中的作用。在具体目标#3中，我们将使用遗传方法定义 PGDH 在正常造血中的作用，特别强调 PGDH 条件性敲除小鼠中造血干细胞的维持和自我更新。更好地了解 PGDH 在癌症与正常干细胞中的非典型功能将提供独特的生物标志物，并有助于通过选择性靶向白血病干细胞同时保留造血干细胞来实现更有效的治疗。 公共健康相关性：本申请中的研究调查了维持白血病干细胞的关键分子途径，白血病干细胞是负责维持造血细胞癌症的关键细胞亚群。特别重点将关注一种酶在癌症干细胞功能中的新作用，该酶原本与前列腺素代谢相关，并且以前与癌症病因无关。更好地了解该因子在癌症与正常干细胞中的独特功能将有助于选择性地研究 针对癌症以获得更有效的治疗方法。