The Role Of CREB In Leukemogenesis

CREB ​​在白血病发生中的作用

• 批准号: 6731871
• 负责人: KATHLEEN M. SAKAMOTO
• 金额: $ 30.36万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-20 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6731871
• 关键词: RNA interference; acute myelogenous leukemia; biological signal transduction; bone marrow transplantation; cAMP response element binding protein; carcinogenesis; cell differentiation; cell proliferation; clinical research; enzyme activity; gel mobility shift assay; genetically modified animals; human subject; laboratory mouse; leukemia; mitogen activated protein kinase; myeloid stem cell; phenotype; protein structure function; western blottings

DESCRIPTION (provided by applicant): Leukemia is the most common form of childhood cancer. Children with acute myeloid leukemia (AML) have less than 50% overall survival despite aggressive chemotherapy and bone marrow transplantation. Therefore, it is critical to understand the molecular pathogenesis of AML. We demonstrated that CREB is overexpressed in bone marrow cells from patients with AML but not in normal bone marrow or bone marrow from patients without active leukemia. Furthermore, CREB overexpression was associated with an increased risk of relapse and decreased event-free survival in patients with AML. Our preliminary results suggest that AML is a heterogeneous disease that is not well understood. We hypothesize that there is an uncoupling of differentiation and CREB expression in myeloid leukemia cells. We propose to study the role of CREB in normal and malignant myeloid cells to identify novel mechanisms of leukemogenesis and improve our understanding of the molecular pathways regulating myeloid cell proliferation and differentiation. In Specific Aim 1, we will characterize CREB expression and activation in primary normal myeloid cells and myeloid leukemia cells. Experiments are proposed to determine the expression of CREB in normal mouse embryos at different stages of hematopoietic development. We will also examine CREB expression in normal myeloid progenitor cells at different stages of myeloid differentiation. Finally, we will examine whether CREB is activated in primary leukemia cells. In Specific Aim 2, we will further characterize the biological phenotype of CREB overexpression and down regulation in myeloid leukemia cell lines and primary normal myeloid cells. Our preliminary results demonstrated that CREB overexpression leads to increased proliferation and survival of myeloid leukemia cells. CREB down regulation using RNA interference (RNAi) suppresses the growth and survival of leukemia cells. To study signaling pathways upstream of CREB, we will overexpress activated kinases and use RNAi technology to inhibit expression of kinases. In Specific Aim 3, we will characterize the phenotype of transgenic mice in which CREB overexpression is targeted to myeloid cells. Defects in hematopoiesis and development of leukemia will be determined in both CREB transgenic mice and a mouse bone marrow transplant model. These studies will define the role of CREB in both normal and malignant myelopoiesis.

描述（由申请人提供）：白血病是儿童癌的最常见形式。急性髓样白血病（AML）的儿童尽管进行了侵略性化疗和骨髓移植，但总生存率少于50％。因此，了解AML的分子发病机理至关重要。我们证明了CREB在AML患者的骨髓细胞中过表达，但没有正常的骨髓或没有活性白血病的患者的骨髓。此外，CREB过表达与AML患者的复发风险增加和无事件生存率降低有关。我们的初步结果表明，AML是一种异质性疾病，尚不清楚。我们假设在髓样白血病细胞中有分化和CREB表达的解耦合。我们建议研究CREB在正常和恶性髓样细胞中的作用，以鉴定白血病的新机制，并提高我们对调节髓样细胞增殖和分化的分子途径的理解。 在特定的目标1中，我们将表征CREB的表达和激活，在原发性正常髓样细胞和髓样白血病细胞中。提出了实验来确定在造血发育的不同阶段正常小鼠胚胎中CREB的表达。我们还将在髓样分化的不同阶段检查正常髓样祖细胞中的CREB表达。最后，我们将检查是否在原发性白血病细胞中激活CREB。在特定目标2中，我们将进一步表征CREB过表达的生物学表型和髓样白血病细胞系和原发性正常髓样细胞中的下降。我们的初步结果表明，CREB的过表达导致髓样白血病细胞的增殖和存活增加。使用RNA干扰（RNAI）调节CREB可抑制白血病细胞的生长和存活。为了研究CREB上游的信号通路，我们将过表达激活的激酶并使用RNAi技术抑制激酶的表达。在特定的目标3中，我们将表征转基因小鼠的表型，其中CREB过表达针对髓样细胞。在CREB转基因小鼠和小鼠骨髓移植模型中，将确定造血和白血病发育的缺陷。这些研究将定义CREB在正常和恶性骨髓中的作用。