The Role of Geminin in Hematopoiesis

描述（由申请人提供）：骨髓中的造血干细胞（hsc）一生中为血液循环提供成熟的血细胞。造血干细胞的分裂既补充了自身的数量，又提供了产生红细胞、白细胞和巨核细胞谱系的固定祖细胞。祖细胞经过有限的分裂，然后分化成成熟的血细胞。祖细胞分裂和分化必须仔细平衡，以提供成熟细胞的正确数量和比例。增生和分化之间的不平衡是常见血液学问题的基础，如白血病、淋巴瘤和骨髓增生异常综合征。尽管它们的重要性显而易见，但控制细胞继续分裂和终末分化之间选择的机制在很大程度上是未知的。本项目将研究调节蛋白Geminin在造血细胞增殖和分化中的作用。双联蛋白是多能性所必需的，被认为是维持分裂细胞处于未分化状态。Geminin是一种双功能蛋白，控制DNA复制的程度并抑制同源结构域（Hox）转录因子，这些转录因子已知是造血的关键调节因子。Geminin敲低激活了Fanconi贫血途径，而在p53-/- T细胞中，Geminin抑制的复制因子Cdt1的过度表达加速了淋巴母细胞淋巴瘤的发展。我们正在使用条件敲除策略来研究Geminin在最终造血中的作用。在干扰素诱导的Mx-1启动子的控制下，将LoxP位点位于gemini基因基本外显子两侧的基因靶向小鼠培育成表达Cre重组酶的小鼠。这些小鼠将接受聚肌苷-多胞苷（poly I:C）处理，以诱导造血细胞中的Cre重组酶并删除Geminin基因。我们将确定Geminin丢失如何影响骨髓中细胞分裂和分化的模式，Geminin如何调节造血细胞的细胞周期，以及Geminin是否抑制白血病或淋巴瘤的发展。我们希望对正常造血有更全面的了解，并为血液系统恶性肿瘤的治疗找到新的靶点。骨髓中的干细胞在人的一生中不断分裂，以产生成熟的血细胞。生长中的血细胞分裂或成熟出现问题会导致白血病和淋巴瘤，这是两种最常见的癌症。该项目研究了双胞蛋白在控制血细胞发育中的作用。

DESCRIPTION (provided by applicant): Hematopoietic stem cells (HSCs) in the bone marrow supply the circulation with mature blood cells throughout life. Division of the HSCs both replenishes their own numbers and provides committed progenitor cells that give rise to the erythrocyte, leukocyte, and megakaryocyte lineages. Progenitor cells undergo a limited number of divisions then differentiate into mature blood cells. Progenitor cell division and differentiation must be carefully balanced in order to provide the correct numbers and proportions of mature cells. Imbalances between proliferation and differentiation underlie common hematological problems like leukemia, lymphoma, and myelodysplastic syndromes. Despite their obvious importance, the mechanisms that control the choice between continued cell division and terminal differentiation are largely unknown. This project will examine the role of the regulatory protein Geminin in the proliferation and differentiation of hematopoietic cells. Geminin is required for pluripotency and is thought to maintain dividing cells in an undifferentiated state. Geminin is a bi-functional protein that controls the extent of DNA replication and inhibits homeodomain (Hox) transcription factors that are known to be crucial regulators of hematopoiesis. Geminin knockdown activates the Fanconi Anemia pathway, and over- expression of the replication factor inhibited by Geminin, Cdt1, in p53-/- T cells accelerates the development of lymphoblastic lymphoma. We are using a conditional knockout strategy to investigate the role of Geminin in definitive hematopoiesis. Gene-targeted mice, in which LoxP sites flank the essential exons of the Geminin gene, are being bred to mice that express Cre recombinase under the control of the interferon-inducible Mx-1 promoter. These mice will be treated with polyinosine- polycytidine (poly I:C) to induce Cre recombinase and delete the Geminin gene in hematopoietic cells. We will determine how Geminin loss affects the pattern of cell division and differentiation in the bone marrow, how Geminin regulates the cell cycle of hematopoietic cells, and whether Geminin suppresses the development of leukemias or lymphomas. We hope to gain a more complete understanding of normal hematopoiesis and identify a new target for therapy of hematological malignancies. PROJECT NARRATIVE Stem cells in the bone marrow continually divide throughout a person's life in order to produce mature blood cells. Problems in the division or the maturation of the growing blood cells give rise to leukemia and lymphoma, two of the most common cancers. This project examines the role of the protein Geminin in controlling blood cell development.