The role of E47 in uncommitted hematopoietic progenitors

描述（由申请人提供）：骨髓造血干细胞在整个成人生活中不断播种血液谱系。E47是一种主要的转录因子，其活性对于未确定的造血祖细胞向淋巴系的进展至关重要。E47表达的紊乱也与血癌有关。我们发现缺乏E47的小鼠骨髓多能祖细胞以及下游谱系限制种群都有严重的耗竭。来自E47缺陷小鼠的原始前体表现出更高的增殖活性，但与分化相关的关键标志物的表达降低。功能获得和功能丧失的互惠研究确定了两个关键基因作为候选E47靶点：细胞周期调节因子p21和转录调节因子Ikaros。在此，我们建议在原发性骨髓前体细胞亚群中建立E47与这两个因子之间的机制关系。在Aim 1中，我们关注增殖缺陷，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Aim 2中，我们研究了E47和p21是否在相同的遗传途径中协同调节干细胞增殖。在Aim 3中，我们确定Ikaros是否是调节原发性多能祖细胞向淋巴系分化的重要E47靶基因。总之，这些目标解决在淋巴系进展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活性失调导致淋巴细胞起源癌症的机制提供关键见解。公共卫生相关性：免疫系统能够对大量潜在病原体作出反应。这部分是通过产生B淋巴细胞和T淋巴细胞来完成的。我们的研究旨在阐明在造血干细胞向淋巴细胞谱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.