p57KIP2 in Hematopoiesis and Leukemogenesis

p57KIP2 在造血和白血病发生中的作用

• 批准号: 7318321
• 负责人: Joseph Michael Scandura
• 金额: $ 9.38万
• 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/7318321
• 关键词: RNA interference; biological signal transduction; carcinogenesis; cell cycle; cell differentiation; cell growth regulation; cell proliferation; clinical research; cyclin dependent kinase; gene expression; genetic transcription; hematopoiesis; hematopoietic stem cells; hematopoietic tissue transplantation; kinase inhibitor; laboratory mouse; leukemia; molecular oncology; neoplasm /cancer genetics; small interfering RNA; stem cell transplantation; transfection; transforming growth factors; tumor suppressor genes

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。p21WAF/CIP1控制正常小鼠造血干细胞的静止，而p27KIP1调节更成熟的祖细胞池。对其他细胞周期蛋白依赖性激酶抑制剂（CDKI）在原发性造血细胞中的功能知之甚少。使用cd34阳性的原代人造血祖细胞/干细胞，我们发现p57KIP2是唯一一个被转化生长因子β (tgfβ)快速且稳健上调的CDKI。我们已经证明这种调节是转录的，是通过近端p57KIP2启动子介导的。p57KIP2的上调对于tgf β诱导的这些细胞生长停滞至关重要，因为阻断p57KIP2上调的两种不同sirna（小干扰RNA）可阻断TGFb对人造血细胞的生长抑制作用。p57 KIP2表达的减少也使造血细胞在缺乏TGFbeta的情况下更容易增殖，TGFbeta对不同的细胞类型和组织具有多效性作用，TGFbeta信号转导失调是恶性细胞的一个重要且常见的特性。正常细胞的原代培养物对tgf - β的生长抑制高度敏感，而大多数恶性细胞和白血病来源的细胞系对这种作用具有抗性。尽管tgf - β信号通路突变在实体肿瘤中出现的频率很高，但它们在白血病中却极为罕见，这表明造血恶性肿瘤中的其他机制失调了这一通路。由此可见，p57KIP2在30%的新发AML病例中沉默可能是重要的。基于我们的研究结果，我们假设p57KIP2在维持干细胞静止和抑制祖细胞扩增中起主要作用。