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: 7867478
• 负责人: Patricia Ernst
• 金额: $ 23.34万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7867478
• 关键词: Adult; Affect; Blood; Blood Cells; Bone Marrow; Cell Death; Cell Survival; Cells; Childhood Acute Lymphocytic Leukemia; Chimeric Proteins; Chromatin; Chromosomal translocation; Commit; Complex; Data; Development; Embryonic Development; Equilibrium; Erythroid; Gene Targeting; Gene-Modified; Genes; Genetic; Goals; Growth; Hematopoiesis; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; Homeostasis; Homing; Individual; Infant; Knock-out; Maintenance; Mediating; Modeling; Molecular; Multipotent Stem Cells; Mus; Nuclear Protein; Nuclear Proteins; Oncogene Proteins; Oncogenes; Output; Pathway interactions; Physiological; Population; Process; Proteins; Regulation; Regulatory Pathway; Research Personnel; Role; Stem cells; System; Testing; Transcript; Work; base; cell type; expectation; in vitro Assay; in vivo; interest; leukemia; leukemogenesis; migration; mutant; progenitor; programs; recombinase; research study; self-renewal; stem; transcription factor

DESCRIPTION (provided by applicant): The Mixed Lineage Leukemia (Mil) gene encodes a chromatin modifying protein that can be deregulated by many different chromosomal translocations to result in leukemia. We have shown that the murine Mil gene is essential for the development of hematopoietic stem cells (HSCs) during embryogenesis, and that a significant overlap exists between the target genes regulated by Mil and its corresponding fusion oncogenes. To understand the functions of Mil within the hematopoietic system, we propose to systematically test the effect of deleting this gene within defined populations of the hematopoietic system. Our preliminary data suggests a profound requirement for Mil in the maintenance of bone marrow hematopoiesis, but the molecular basis for this requirement or the precise cell types affected is not known. We propose to 1) utilize a conditional knockout model to determine whether Mil regulates HSCs in the bone marrow through effects on self-renewal, proliferation or homing/migration, 2) identify M/-dependent processes that maintain multipotent progenitors, and 3) whether re-expression of individual Hox target genes replace these functions Our long-term goals are to understand the genetic networks that operate to balance HSC self-renewal, proliferation/quiescence and differentiation. In particular we are interested in how the MII-Hox pathway integrates with other known transcriptional regulatory pathways to regulate hematopoiesis. Furthermore, it is our expectation that by dissecting the precise role of Mil in hematopoiesis, we will understand better how to target MLL fusion oncogenes that deregulate these normal processes. Relevance: Our work is focused on understanding the gene regulatory pathways that control the identity and function of hematopoetic stem cells and their differentiated progeny. The same regulatory pathways are perturbed in leukemia, so understanding the regulation of these pathways will be essential for devising new strategies to treat leukemia.

描述(申请人提供)：混合血统白血病(MIL)基因编码一种染色质修饰蛋白，可通过许多不同的染色体易位来解除调节，从而导致白血病。我们已经证明，小鼠MIL基因在胚胎发育过程中对造血干细胞(HSCs)的发育是必不可少的，并且MIL调控的靶基因与其相应的融合癌基因之间存在显著的重叠。为了了解MIL在造血系统中的功能，我们建议在造血系统的特定人群中系统地测试删除该基因的效果。我们的初步数据表明，MIL在维持骨髓造血方面有着深刻的需求，但这一需求的分子基础或受影响的确切细胞类型尚不清楚。我们建议1)利用条件基因敲除模型来确定MIL是否通过对自我更新、增殖或归巢/迁移的影响来调节骨髓中的HSC，2)确定维持多潜能祖细胞的M/依赖过程，以及3)单个HOX靶基因的重新表达是否取代这些功能我们的长期目标是了解运行的遗传网络来平衡HSC的自我更新、增殖/静止和分化。特别是，我们感兴趣的是Mii-Hox通路如何与其他已知的转录调控通路结合来调控造血。此外，我们期望通过剖析MIL在造血中的确切作用，我们将更好地了解如何靶向破坏这些正常过程的MLL融合癌基因。相关性：我们的工作重点是了解控制造血干细胞及其分化后代的身份和功能的基因调控途径。同样的调节通路在白血病中也受到干扰，因此了解这些通路的调节对于设计治疗白血病的新策略至关重要。