The role of E47 in uncommitted hematopoietic progenitors

描述(申请人提供)：骨髓造血干细胞在成人一生中不断地为血统播种。E47是一种主要的转录因子，其活性对未定向造血祖细胞向淋巴系的发展至关重要。E47基因表达的紊乱也与血癌有关。我们发现，缺乏E47的小鼠有严重的骨髓多能祖细胞枯竭以及下游血统受限的种群。来自E47缺陷小鼠的原始前体细胞表现出高度的增殖活性，但与分化相关的关键标志的表达减少。功能互补和功能丧失研究确定了两个关键基因作为候选的E47靶点：细胞周期调控因子p21和转录调控因子Ikaros。在这里，我们建议在初级骨髓前体亚群中建立E47和这两个因素之间的机制关系。在目标1中，我们将重点放在增殖性缺陷上，并确定E47是否是干细胞增殖和自我更新之间平衡的关键调节因子。在目标2中，我们检查了E47和p21是否在相同的遗传途径中协作来调节干细胞的增殖。在目标3中，我们确定Ikaros是否是调节原始多能祖细胞向淋巴系分化的必需的E47靶基因。总之，这些目标解决了在淋巴系进化过程中调节干细胞功能完整性的分子机制。这项工作将提供有关控制干细胞完整性的分子事件的新信息，并将为E47活性失调导致淋巴源性癌症的机制提供关键的见解。公共卫生相关性：免疫系统能够对大量潜在病原体做出反应。这在一定程度上是通过产生B和T淋巴细胞来实现的。我们的研究旨在阐明在向淋巴细胞系发展过程中调节造血干细胞功能完整性的因素。

DESCRIPTION (provided by applicant): Bone marrow hematopoietic stem cells continually seed the blood lineages throughout adult life. E47 is a major transcription factor whose activity is critical for the progression of uncommitted hematopoietic progenitors to the lymphoid lineages. Perturbations in E47 expression are also associated with blood cancers. We have found that mice lacking E47 have a profound depletion of bone marrow multipotent progenitors as well downstream lineage restricted populations. Primitive precursors from E47 deficient mice exhibit heightened proliferative activity but decreased expression of key markers associated with differentiation. Reciprocal gain of function and loss of function studies identify two key genes as candidate E47 targets: the cell cycle regulator p21 and the transcriptional regulator Ikaros. Here, we propose to establish the mechanistic relationship between E47 and these two factors in primary bone marrow precursor subsets. In Aim 1, we focus on the proliferative defect and determine if E47 is a critical regulator of the balance between stem cell proliferation and self-renewal. In Aim 2, we examine whether E47 and p21 collaborate in the same genetic pathway to regulate stem cell proliferation. In Aim 3, we determine if Ikaros is the essential E47 target gene that regulates the differentiation of primary multipotent progenitors to the lymphoid lineages. Together, these aims address the molecular mechanisms that regulate the functional integrity of stem cells during lymphoid lineage progression. This work will provide new information about the molecular events that control stem cell integrity, and will provide key insight into the mechanisms by which dysregulation of E47 activity contributes to cancers of lymphoid origin. Public Health Relevance: The immune system is capable of responding to a vast array of potential pathogens. This is accomplished in part through the production of B and T lymphocytes. Our studies are aimed at elucidating the factors that regulate the functional integrity of hematopoietic stem cells during progression to the lymphocyte lineages.