Role of PGDH in leukemia pathogenesis

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。我们最近发现PGDH（NAD+-依赖性15-羟基前列腺素脱氢酶）是一种参与前列腺素代谢失活的关键酶，与急性白血病的主要发病机制有关。它在白血病干细胞中高度表达，并在调节白血病干细胞自我更新的MLL/HOX通路中作为关键介质。PGDH的相关作用是非常出乎意料的，因为它以前没有与促成癌症因果关系相关，这与早期提出的保护作用形成对比。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，因此推断PGDH具有以前未知的非经典和新的生化功能。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经典作用的机制。在小鼠模型系统中使用功能获得遗传学方法，我们将进行结构/功能研究以鉴定PGDH的白血病特异性功能域。这将指导后续的生化研究，以确定蛋白质，特别是与PGDH致癌贡献所需的基本结构域。特定目标#2研究将使用急性白血病小鼠模型以及人白血病细胞系和细胞的组合来定义白血病干细胞中PGDH维持的分子途径。受PGDH影响的分子途径将使用高通量表达谱分析技术结合高端生物信息学进行表征，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。对PGDH在癌症与正常干细胞中的非典型功能的更深入了解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。

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.