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

• 批准号: 8514050
• 负责人: Alexander C Minella
• 金额: $ 35.55万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8514050
• 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 Proliferation; 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; Gene Expression; Genes; Genomic Instability; Goals; Health; 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; Phenotype; Phosphorylation; Physiological; Play; Protein p53; Proteins; Refractory anemias; Regulation; Research Personnel; Role; S Phase; Signal Pathway; Staging; Stem cells; Stress; 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

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）：血细胞发育依赖于精确控制的基因表达程序，该程序控制祖细胞沿着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正常血细胞成熟至关重要。在小鼠基因敲入模型中，我们发现异常的红细胞成熟，增加增殖，凋亡和发育不良的形态在红系祖细胞中，以研究失调的细胞周期蛋白E，调节S期进入的蛋白质的生理后果。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。我们推测，在正常造血过程中，细胞周期蛋白E的适当调节是至关重要的，而细胞周期调控失调有助于血液疾病如MDS和白血病的发病机制。Fbw 7泛素连接酶是细胞周期蛋白E活性的主要调节因子，也控制着参与细胞生长和增殖的其他重要致癌蛋白的丰度。Fbw 7功能缺失突变见于急性白血病，与骨髓增生异常和白血病相关的信号通路突变可损害Fbw 7介导的细胞周期蛋白E降解。我们最近发现，在红系祖细胞中，p53肿瘤抑制因子在对受损的Fbw 7介导的细胞周期蛋白E降解的DNA损伤型反应中被激活。在包括目标1的拟议研究中，我们将首先确定细胞周期蛋白E及其引起的分子反应如何改变正常红系细胞成熟。MDS是由造血干细胞缺陷引起的一组异质性血液疾病。在目标2中提出的研究中，我们将检验Fbw 7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。在晚期MDS中发现了p53突变，其与进展为坦率的白血病相关。在目标3中，我们将检验以下假设：受损的p53功能与造血祖细胞中失调的细胞周期蛋白E协同诱导体内肿瘤形成。我们将开发小鼠骨髓移植模型来测试这一假设，通过禁用p53功能在细胞周期蛋白E敲入造血细胞，直接通过等位基因缺失或间接通过表达失调的另一个致癌底物Fbw 7，c-Jun。公共卫生相关性：骨髓增生异常综合征和急性白血病，从MDS发展是特别难以治疗的，通常会导致死亡。有迫切需要更好地了解这些疾病的分子发病机制，这些研究的一个长期目标，以便设计更有效的治疗策略。 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”），当它被异常调节时，会导致血细胞发育缺陷，其中一些类似于在一些骨髓增生异常患者中发现的缺陷。研究人员现在建议研究高水平的细胞周期蛋白E是如何导致这些血细胞缺陷并导致骨髓衰竭和癌症的。