Cyclin E Regulation in Normal and Neoplastic Hematopoiesis

正常和肿瘤造血中的细胞周期蛋白 E 调节

基本信息

批准号：
7984791
负责人：
Alexander C Minella
金额：
$ 37.75万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7984791
关键词：
Abnormal Red Blood Cell Acute leukemia Animals Apoptosis Apoptotic Biological Assay Blood Cells Bone Marrow Transplantation Cause of Death Cell Aging Cell Cycle Regulation Cell Maturation Cell division Cell physiology Cells Characteristics Cyclin E Cyclin E Degradation Pathway Cyclins DNA Damage Defect Development Disabled Persons Disease Dysmyelopoietic Syndromes Elderly Erythroid Erythroid Cells Erythroid Progenitor Cells Erythropoiesis Event Exhibits Future G1 Phase Gene Expression Genes Genomic Instability Goals Hematologic Neoplasms Hematological Disease Hematopoiesis Hematopoietic Hematopoietic stem cells Impairment In Vitro Induction of Apoptosis JUN gene Knock-in Mouse Learning Lesion Malignant - descriptor Malignant Neoplasms Mediating Modeling Molecular Morphology Mus Mutation Neoplasms Oncogenic Pancytopenia Pathogenesis Pathway interactions Patients Phase Phenotype Phosphorylation Physiological Play Protein p53 Proteins Refractory anemias Regulation Research Personnel Role Signal Pathway Staging Stem cells Stress TP53 gene Testing Threonine Transplantation Ubiquitination cell growth disease phenotype effective therapy erythroid differentiation exhaustion hematopoietic tissue in vivo inhibitor/antagonist leukemia loss of function mutation neoplastic progenitor programs public health relevance response transcription factor treatment strategy ubiquitin ligase

项目摘要

DESCRIPTION (provided by applicant): Blood cell development depends on precisely controlled gene expression programs that govern the commitment and maturation of progenitor cells along specific lineages. In addition to transcription factors that regulate gene expression during the course of lineage commitment, intact cell cycle control mechanisms are critical to normal blood cell maturation. In a mouse knock-in model developed to study the physiologic consequences of dysregulated cyclin E, a protein that regulates S-phase entry, we found abnormal red blood cell maturation, with increased proliferation, apoptosis, and dysplastic morphologies in erythroid progenitors. These features are characteristics of hematopoietic cells of patients with early-stage myelodysplastic syndromes (MDS). We hypothesize that proper regulation of cyclin E is critical during normal hematopoiesis and that deregulated cell cycle controls contribute to the pathogenesis of blood diseases such as MDS and leukemia. The Fbw7 ubiquitin ligase is a major regulator of cyclin E activity and also controls the abundance of other important oncogenic proteins involved in cell growth and proliferation. Fbw7 loss-of-function mutations are found in acute leukemias, and mutations in signaling pathways associated with myelodysplasia and leukemias can impair Fbw7- mediated cyclin E degradation. We recently found that the p53 tumor suppressor is activated in erythroid progenitor cells in a DNA damage-type response to impaired Fbw7-mediated cyclin E degradation. In the proposed studies comprising Aim 1, we will first define how high cyclin E and the molecular response it evokes alters normal erythroid cell maturation. MDS is a heterogeneous group of blood diseases caused by hematopoietic stem cell defects. In studies proposed in Aim 2, we will test the hypothesis that Fbw7-mediated cyclin E regulation critically maintains normal hematopoietic stem cell function. Mutations in p53 are found in advanced stage MDS, which is associated with progression to frank leukemia. In Aim 3, we will test the hypothesis that compromised p53 function cooperates with dysregulated cyclin E in hematopoietic progenitors to induce neoplasia in vivo. We will develop mouse marrow transplantation models to test this hypothesis by disabling p53 function in cyclin E knock-in hematopoietic cells, either directly by allelic deletion or indirectly via dysregulated expression of another oncogenic substrate of Fbw7, c-Jun. PUBLIC HEALTH RELEVANCE: Myelodysplastic syndromes and acute leukemias that evolve from MDS are especially difficult to treat, usually causing death. There is urgent need for a better understanding of the molecular pathogenesis of these diseases, one long-term goal of these studies, in order for more effective treatment strategies to be devised. PUBLIC HEALTH RELEVANCE: Myelodysplastic syndromes and acute leukemias are malignant diseases of the blood, and in older adults these diseases are especially difficult to treat and usually cause death. There is urgent need for understanding the different ways in which these diseases occur so that better treatments can be developed in the future. The investigators recently found that one of the proteins that controls cell division (called "cyclin E"), when it is abnormally regulated, causes defects in blood cell development, some of which resemble those found in some patients with myelodysplasia. The investigators now propose to study how high cyclin E levels cause these blood cell defects and contribute to bone marrow failure and cancers.

描述（由申请人提供）：血细胞发育取决于精确控制的基因表达程序，该程序控制祖细胞沿特定谱系的定型和成熟。除了在谱系定型过程中调节基因表达的转录因子外，完整的细胞周期控制机制对于正常血细胞成熟也至关重要。在为研究细胞周期蛋白E（一种调节S期进入的蛋白质）失调的生理后果而开发的小鼠敲入模型中，我们发现红细胞成熟异常，红细胞祖细胞增殖、凋亡和发育异常形态增加。这些特征是早期骨髓增生异常综合征（MDS）患者造血细胞的特征。我们假设细胞周期蛋白 E 的正确调节在正常造血过程中至关重要，而细胞周期控制失调则导致 MDS 和白血病等血液疾病的发病机制。 Fbw7 泛素连接酶是细胞周期蛋白 E 活性的主要调节因子，还控制参与细胞生长和增殖的其他重要致癌蛋白的丰度。 Fbw7 功能丧失突变存在于急性白血病中，与骨髓增生异常和白血病相关的信号通路突变可能会损害 Fbw7 介导的细胞周期蛋白 E 降解。我们最近发现，在对 Fbw7 介导的细胞周期蛋白 E 降解受损的 DNA 损伤型反应中，p53 肿瘤抑制因子在红系祖细胞中被激活。在包括目标 1 的拟议研究中，我们将首先定义高细胞周期蛋白 E 及其引起的分子反应如何改变正常红细胞成熟。 MDS是一组由造血干细胞缺陷引起的异质性血液疾病。在目标 2 提出的研究中，我们将检验 Fbw7 介导的细胞周期蛋白 E 调节关键维持正常造血干细胞功能的假设。 p53 突变发现于晚期 MDS，这与进展为明确的白血病有关。在目标 3 中，我们将检验以下假设：p53 功能受损与造血祖细胞中细胞周期蛋白 E 失调共同诱导体内肿瘤形成。我们将开发小鼠骨髓移植模型，通过直接通过等位基因删除或间接通过 Fbw7 的另一种致癌底物 c-Jun 的表达失调来禁用细胞周期蛋白 E 敲入造血细胞中的 p53 功能来测试这一假设。公共卫生相关性：由 MDS 演变而来的骨髓增生异常综合征和急性白血病特别难以治疗，通常会导致死亡。迫切需要更好地了解这些疾病的分子发病机制，这是这些研究的长期目标之一，以便设计出更有效的治疗策略。公共卫生相关性：骨髓增生异常综合征和急性白血病是恶性血液疾病，在老年人中，这些疾病特别难以治疗，通常会导致死亡。迫切需要了解这些疾病发生的不同方式，以便将来开发出更好的治疗方法。研究人员最近发现，一种控制细胞分裂的蛋白质（称为“细胞周期蛋白E”）如果受到异常调节，会导致血细胞发育缺陷，其中一些缺陷类似于一些骨髓增生异常患者中发现的缺陷。研究人员现在提议研究高细胞周期蛋白 E 水平如何导致这些血细胞缺陷并导致骨髓衰竭和癌症。