p57KIP2 in Hematopoiesis and Leukemogenesis

p57KIP2 在造血和白血病发生中的作用

• 批准号: 6868998
• 负责人: Joseph Michael Scandura
• 金额: $ 13.47万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 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/6868998
• 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（由申请人提供）：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 控制正常的小鼠造血干细胞静止，而 p27KIP1 则调节更成熟的祖细胞库。对于其他细胞周期蛋白依赖性激酶抑制剂 (CDKI) 在原代造血细胞中发挥的功能知之甚少。使用 CD34 阳性的原代人类造血祖细胞/干细胞，我们已确定 p57KIP2 是唯一能通过转化生长因子 β (TGFbeta) 快速而有力地上调的 CDKI。我们已经证明这种调节是转录性的，并且是通过近端 p57KIP2 启动子介导的。 p57KIP2 的上调对于 TGFbeta 诱导的这些细胞的生长停滞至关重要，因为阻断 p57KIP2 上调的两种不同 siRNA（小干扰 RNA）会阻断 TGFb 对人类造血细胞的生长抑制作用。 p57 KIP2 表达的减少还使得造血细胞在没有 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，并且 TGFbeta 信号转导失调是恶性细胞的重要且常见的特性。虽然正常细胞的原代培养物对 TGFbeta 的生长抑制高度敏感，但大多数恶性细胞和白血病来源的细胞系对此效果具有抵抗力。尽管 TGFbeta 信号通路中的突变在实体瘤中频繁出现，但在白血病中极为罕见，这表明其他机制在造血系统恶性肿瘤中失调了该通路。有鉴于此，p57KIP2 在 30% 的新发 AML 病例中被沉默可能具有重要意义。根据我们的发现，我们假设 p57KIP2 在维持干细胞静止和抑制祖细胞扩张中发挥重要作用。 为了检验这一假设，我们提出以下建议：1) 定义 p57KIP2 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TGFb上调造血细胞中p57KIP2转录的机制； 3) 评估 p57KIP2 在造血系统恶性肿瘤中的肿瘤抑制活性。