SELF-RENEWAL IN LEUKEMIC STEM CELLS

白血病干细胞的自我更新

• 批准号: 7864588
• 负责人: Li Chai
• 金额: $ 26.61万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7864588
• 关键词: Accounting; Acute Myelocytic Leukemia; Apoptosis; Apoptotic; Blood Platelets; Bone Marrow; Bone Marrow Cells; Bone Marrow Transplantation; Cell Line; Cells; Chemotherapy-Oncologic Procedure; Death Rate; Development; Down-Regulation; Drug resistance; Elements; Erythrocytes; Figs - dietary; Genes; Growth; Hematopoiesis; Hematopoietic Neoplasms; Hematopoietic stem cells; Human; Incidence; Knock-out; Leukemic Cell; Malignant Neoplasms; Modeling; Molecular; Mus; Oncogenes; Phenotype; Play; Property; Protein Isoforms; Relapse; Role; Signal Pathway; Stem cells; Structure; Testing; Transgenic Mice; Transplantation; United States; Up-Regulation; base; chemotherapy; combat; effective therapy; gain of function; in vivo; leukemia; leukemogenesis; mortality; mouse model; neutrophil; novel; novel strategies; pluripotency; public health relevance; research study; self-renewal

DESCRIPTION (provided by applicant): Our long-term objectives are to advance the understanding of the molecular mechanism(s) that govern the self-renewal property of leukemic stem cells (LSCs). LSCs are cells that can give rise to leukemia in transplant models, and therefore have self-renewal properties. It is hypothesized that these cells are not targeted under current chemotherapy regimens and therefore account for drug resistance and leukemia relapse. Identifying genes or signaling pathways involved in the self-renewal of LSCs will likely promote the development of more effective treatments for leukemia and other cancers. Bmi-1 is a key element involved in LSC self-renewal, and is aberrantly upregulated in LSCs. The underlying cause(s) for deregulation of Bmi-1 in LSCs remain unknown. We have discovered that SALL4, a newly identified pluripotency factor and a novel oncogene, is aberrantly expressed in human acute myeloid leukemia (AML). Transgenic mice that mimic this aberrant expression of SALL4B, one of the SALL4 isoforms, develop AML.8 Further studies on these SALL4B mice have led to the identification and characterization of LSCs in the SALL4B-induced AML mouse model. Parallel to gain-of-function studies, knockdown of SALL4 expression in leukemic cell lines triggers cell apoptosis and growth arrest. While upregulation of Bmi-1 is found in the SALL4B-induced LSCs, downregulation of SALL4 leads to decreased expression of Bmi-1. Restoring Bmi-1 expression in SALL4 knockdown leukemic cell lines rescues the apoptotic phenotype. More detailed studies have demonstrates that Bmi-1 is a direct target of SALL4 in bone marrow cells. Based on these findings, we hypothesize that deregulation of SALL4B plays a key role in promoting self-renewal of LSCs by activation of Bmi-1. To prove this hypothesis, I propose to 1) Determine the functional role(s) of SALL4 in self-renewal of normal hematopoietic stem cell (HSCs) and LSCs; and 2) Define the mechanism of SALL4 enhancement of self-renewal of HSCs and LSCs with a focus on its up-regulation of Bmi-1. These two groups of experiments will serve to better understand the critical mechanism(s) in leukemogenesis, and potentially develop novel strategies to combat leukemia. PUBLIC HEALTH RELEVANCE: In United States, there are 33,000 new cases of leukemia (blood cancer) with a death rate of 23,000 every year. Despite chemotherapy and bone marrow transplantation, most leukemia relapses and has a high-mortality rate. One recent approach to decrease the incidence of relapse involves targeting "leukemic stem cell (LSC)", and we propose to test the functional role of a novel oncogene SALL4 in LSCs and its potential usage in treating leukemia.

描述（由申请人提供）：我们的长期目标是促进对控制白血病干细胞（LSCs）自我更新特性的分子机制的理解。在移植模型中，LSCs是可以引起白血病的细胞，因此具有自我更新的特性。据推测，在目前的化疗方案下，这些细胞不是靶向的，因此可以解释耐药性和白血病复发。识别与LSCs自我更新有关的基因或信号通路可能会促进白血病和其他癌症更有效治疗方法的发展。Bmi-1是参与LSC自我更新的关键因素，在LSC中异常上调。LSCs中Bmi-1失调的根本原因尚不清楚。我们发现SALL4是一种新发现的多能因子和一种新的致癌基因，在人类急性髓性白血病（AML）中异常表达。模仿SALL4B （SALL4亚型之一）异常表达的转基因小鼠发展为AML。8对这些SALL4B小鼠的进一步研究导致了SALL4B诱导的AML小鼠模型中LSCs的鉴定和表征。与功能获得性研究平行，在白血病细胞系中敲低SALL4表达可触发细胞凋亡和生长停滞。虽然在sall4b诱导的LSCs中发现Bmi-1上调，但SALL4下调导致Bmi-1表达降低。恢复SALL4敲除白血病细胞系中Bmi-1的表达可挽救凋亡表型。更详细的研究表明，Bmi-1是骨髓细胞中SALL4的直接靶点。基于这些发现，我们假设SALL4B的失调通过激活Bmi-1在促进LSCs自我更新中起着关键作用。为了证明这一假设，我建议：1)确定SALL4在正常造血干细胞（hsc）和LSCs自我更新中的功能作用；2)明确SALL4增强hsc和LSCs自我更新的机制，重点关注其上调Bmi-1。这两组实验将有助于更好地了解白血病发生的关键机制，并有可能开发出对抗白血病的新策略。公共卫生相关性：在美国，每年有33,000例新的白血病（血癌）病例，死亡率为23,000例。尽管有化疗和骨髓移植，大多数白血病还是会复发，而且死亡率很高。最近一种降低复发发生率的方法涉及靶向“白血病干细胞（LSC）”，我们建议测试一种新的致癌基因SALL4在LSC中的功能作用及其在治疗白血病中的潜在用途。