MLL Function in the Maintenance of the Blood Forming System

MLL 在维持造血系统中的功能

• 批准号: 8974685
• 负责人: Patricia Ernst
• 金额: $ 38.1万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-11-22 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8974685
• 关键词: MLL; Function; Maintenance; Blood; Forming

Project Summary Hematopoietic stem cells (HSCs) represent one of the most flexible and well-studied tissue stem cells in mammals, and are clinically important for the treatment of hematologic malignancies, congenital bone marrow syndromes, and other malignancies. Our understanding of the molecular pathways that underlie the self-renewal versus differentiation decisions is insufficient to allow us to safely manipulate HSCs for clinical benefit. Our preliminary studies and published work demonstrates that the Mixed Lineage Leukemia (MLL) protein is essential for sustaining HSCs during development and homeostasis. We have developed and utilized conditional gene ablation approaches to define a window of development in which HSCs become dependent on MLL for their expansion. This window coincides with the establishment of hematopoiesis in the bone marrow. We have also identified a small, unique network of genes in adult HSCs that we hypothesize are direct transcriptional targets of MLL and are important effectors of its HSC maintenance function. Our overall objective is to define the genetic network within which MLL operates in fetal and adult HSCs, since key features of HSC function, proliferation and self-renewal are distinct between these two developmental periods. To achieve this objective, we will: 1) identify MLL-dependent genes in murine fetal HSCs and compare these to our adult HSC data, 2) determine the pattern of MLL binding in fetal HSCs using human HSC-enriched populations, 3) determine the niche and developmental stage defining the beginning of MLL dependent HSC expansion/homeostasis, and 4) define the MLL-dependent transcriptional network and mechanisms that operate in adult murine HSCs to promote self-renewal. Accomplishing these aims will result in important new insights into a critical but understudied pathway that regulates HSC function and self-renewal. By using the best features of human and mouse model systems, and combining state-of-the-art molecular and genomic techniques with rigorous developmental studies, we hope to discover safe and effective means to manipulate HSCs for clinical benefit.

项目摘要 造血干细胞（HSC）代表了最柔软，最精心良好的组织干细胞之一 在哺乳动物中，对于治疗血液系统恶性肿瘤，在临床上很重要，先天性 骨髓综合征和其他恶性肿瘤。我们对分子途径的理解 基于自我更新与差异化决策的基础不足以让我们安全 操纵HSC以获得临床益处。我们的初步研究和发表的工作表明 混合谱系白血病（MLL）蛋白对于在发育过程中维持HSC至关重要 稳态。我们已经开发并利用条件基因消融方法来定义 HSC依赖于MLL的扩展的发展窗口。这个窗口 与在骨髓中建立造血作用相吻合。我们还确定了 我们假设的成人HSC中小的，独特的基因网络是直接转录目标 MLL，是其HSC维护功能的重要效应因素。我们的总体目标是定义 MLL在胎儿和成人HSC中运行的遗传网络，因为HSC的关键特征 这两个发展期之间的功能，增殖和自我更新是不同的。到 实现此目标，我们将：1）确定鼠胎胎HSC中的MLL依赖性基因并进行比较 这些对我们的成人HSC数据，2）使用人类确定胎儿HSC中MLL结合的模式 富含HSC的人群，3）确定定义开始的利基市场和发展阶段 依赖于MLL的HSC扩展/稳态，4）定义依赖MLL的转录。 在成年鼠HSC中运行以促进自我更新的网络和机制。完成 这些目标将导致对一条调节的关键但经过研究的途径的重要新见解 HSC功能和自我更新。通过使用人类和鼠标模型系统的最佳功能，以及 将最先进的分子和基因组技术与严格的发展研究相结合， 我们希望发现安全有效的手段来操纵HSC以临床利益。