p57KIP2 in Hematopoiesis and Leukemogenesis

p57KIP2 在造血和白血病发生中的作用

• 批准号: 7383152
• 负责人: Joseph Michael Scandura
• 金额: $ 13.47万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7383152
• 关键词: Acute; Acute Lymphocytic Leukemia; Acute Myelocytic Leukemia; Affect; B-Cell Lymphomas; Blood Cells; CD34 gene; CDKN1C gene; Cell Cycle Regulation; Cell Line; Cell Lineage; Cell Proliferation; Cell physiology; Cells; Chimeric Proteins; Chronic Lymphocytic Leukemia; Cyclin-Dependent Kinase Inhibitor; Doctor of Philosophy; Frequencies; Gene Transfer; Genetic Transcription; Growth; Hematopoiesis; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic stem cells; Human; In Vitro; Knockout Mice; Light; Localized; Maintenance; Malignant Neoplasms; Mediating; Mus; Mutation; Myeloid Leukemia; Normal Cell; Organism; Pathway interactions; Patients; Penetrance; Phenotype; Play; Process; Proliferating; Property; Regulation; Resistance; Retroviridae; Role; Series; Signal Pathway; Signal Transduction; Small Interfering RNA; Solid Neoplasm; Stem cells; Testing; Tissues; Transforming Growth Factor beta; Transplantation; Tumor Suppressor Proteins; Up-Regulation; base; cancer cell; cell type; in vivo; leukemia; leukemogenesis; mutant; oncoprotein p21; p27 Cell Cycle Protein; p27 Enzyme Inhibitor; progenitor; promoter; self-renewal; stem; transcription factor

DESCRIPTION (provided by applicant): An intimate relationship exists between cell cycle regulation and hematopoietic progenitor and stem cell function. While p21WAF/CIP1 controls normal murine hematopoietic stem cell quiescence, p27KIP1 regulates the pool of more mature progenitors. Little is known of the function performed by other cyclin dependent kinase inhibitors (CDKI) in primary hematopoietic cells. Using CD34-positive, primary, human hematopoietic progenitor/stem cells, we have identified p57KIP2 as the only CDKI rapidly and robustly upregulated by transforming growth factor beta (TGFbeta). We have shown that this regulation is transcriptional and is mediated through the proximal p57KIP2 promoter. The upregulation of p57KIP2 is essential for TGFbeta-induced growth arrest in these cells as two different siRNAs (small interfering RNA) that block p57KIP2 upregulation block the growth inhibitory effects of TGFb on human hematopoietic cells. Reduction of p57 KIP2 expression also allows hematopoietic cells to proliferate more readily in the absence of TGFbeta, TGFbeta has pleiotropic effects on diverse cell types and tissues and dysregulated TGFbeta signal transduction is an important, and common, property of malignant cells. Whereas primary cultures of normal cells are highly sensitive to growth-inhibition by TGFbeta, most malignant cells and leukemia-derived cell lines are resistant to this effect. Despite the frequency with which mutations in the TGFbeta signaling pathway arise in solid tumors, they are exceedingly uncommon in leukemias suggesting that other mechanisms dysregulate this pathway in the hematopoietic malignancies. In this light, it may be significant that p57KIP2 is silenced in 30% of de novo AML cases. Based upon our findings, we hypothesize that p57KIP2 plays a major role in the maintenance of stem cell quiescence and in restraining progenitor expansion. To test this hypothesis we propose the following: 1) To define the role of p57KIP2 in normal hematopoietic progenitor/stem cell proliferation, differentiation and self-renewal; 2) To determine the mechanism by which TGFb upregulates the transcription of p57KIP2 in hematopoietic cells; and 3) To assess the tumor-suppressor activity of p57KIP2 in hematopoietic malignancies.

描述（申请人提供）：细胞周期调节与造血祖细胞和干细胞功能之间存在密切关系。虽然p21 WAF/CIP 1控制正常的小鼠造血干细胞静止，但p27 KIP 1调节更成熟的祖细胞库。其他细胞周期蛋白依赖性激酶抑制剂（CDKI）在原代造血细胞中的功能知之甚少。使用CD 34阳性的原代人造血祖细胞/干细胞，我们已经鉴定出p57 KIP 2是唯一被转化生长因子β（TGF β）快速和强烈上调的CDKI。我们已经表明，这种调节是转录和介导的近端p57 KIP 2启动子。p57 KIP 2的上调对于这些细胞中TGF β诱导的生长停滞是必需的，因为阻断p57 KIP 2上调的两种不同的siRNA（小干扰RNA）阻断TGF β对人造血细胞的生长抑制作用。p57 KIP 2表达的减少还允许造血细胞在TGF β不存在的情况下更容易增殖，TGF β对不同的细胞类型和组织具有多效性作用，并且失调的TGF β信号转导是恶性细胞的重要且常见的性质。尽管正常细胞的原代培养物对TGF β的生长抑制高度敏感，但大多数恶性细胞和白血病衍生的细胞系对这种作用具有抗性。尽管TGF β信号传导途径突变在实体瘤中出现的频率很高，但它们在白血病中非常罕见，表明造血系统恶性肿瘤中其他机制失调了该途径。因此，在30%的原发AML病例中p57 KIP 2沉默可能是重要的。基于我们的研究结果，我们假设p57 KIP 2在维持干细胞静止和抑制祖细胞扩增中起着重要作用。 为了验证这一假设，我们提出了以下几点：1）确定p57 KIP 2在正常造血祖细胞/干细胞增殖、分化和自我更新中的作用; 2）确定TGF β上调造血细胞中p57 KIP 2转录的机制; 3）评估p57 KIP 2在造血恶性肿瘤中的肿瘤抑制活性。