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（由申请人提供）：混合谱系白血病（MIL）基因编码一种染色质修饰的蛋白质，可以通过许多不同的染色体易位来消除，从而导致白血病。我们已经表明，鼠基因在胚胎发生过程中对于造血干细胞（HSC）的发展至关重要，并且在由MIL调节的靶基因及其相应的融合致癌基因之间存在显着的重叠。为了了解造血系统中MIL的功能，我们建议系统地测试在造血系统定义的种群中删除该基因的效果。我们的初步数据表明，对维持骨髓造血的MIL有很大的要求，但是该需求的分子基础或受影响的精确细胞类型的分子基础尚不清楚。我们建议1）利用条件敲除模型来确定MIL是否通过对自我更新，增殖或归因/迁移的影响来调节骨髓中的HSC是否是否调节HSC，2）确定依赖M/依赖性的过程以维持多型祖细胞，以及3）3）是否会重新表达这些hox目标基因的长期替换为替代HISSSS的人，从而替代了HESSC，以平衡HHSSSS，以平衡HHSSSS，以平衡HHSSSC，这是平衡的概念，可以平衡HHSSC的平衡，以平衡HHSSC，增殖/静止和分化。特别是我们对MII-HOX途径如何与其他已知的转录调节途径整合以调节造血的途径感兴趣。此外，我们期望通过剖析MIL在造血中的精确作用，我们将更好地理解如何靶向消除这些正常过程的MLL融合肿瘤基因。相关性：我们的工作专注于理解控制血压干细胞及其分化后代的身份和功能的基因调节途径。在白血病中，相同的调节途径也受到干扰，因此了解这些途径的调节对于制定新的治疗白血病的策略至关重要。