Alox5基因及其相关通路基因调控慢性髓系白血病干细胞的分子机制研究

Human chronic myeloid leukemia is the most common myeloproliferative disorders, a curative cancer therapy of CML requires eradication of cancer stem cells， In this application, we try to understand the regulatory mechanisms of cancer stem cells for developing effective, selective therapies through targeting cancer stem cells.In this application, we study leukemia stem cells (LSCs) in an efficient and faithful mouse model of human chronic myeloid leukemia (CML) induced by the BCR-ABL oncogene. CML serves as an excellent model disease for studying the biology and molecular signaling of cancer stem cells. Traditional medcine does not eradicate LSCs, so there is an urgent need for developing curative chemotherapy regimens for CML, and the development of such regimens relies on identification of critical genes in LSCs and understanding of their underlying mechanisms. Our proposed studies in this application will follow our recently published findings that the survival and self-renewal of LSCs but not normal hematopoietic stem cells require the arachidonate 5-lipoxygenase (5-LO) gene (Alox5) and that Alox5 is essential for CML development. Our preliminary studies show that Alox5 regulates a molecular network consisting two groups of genes (positive and negative regulatory genes) in LSCs and that it is feasible to specifically target LSCs while sparing their normal stem cell counterparts. Alox5 represents a major molecular pathway in LSCs, and it will be critical to fully understand how Alox5 interacts with its downstream genes in LSCs to help to create a promising anti-stem cell strategy for curative therapy of CML. The specific aims are to study whether Alox5 regulates the function of LSCs through leukotrienes produced by the Alox5 gene product 5-LO; to study the molecular mechanisms for Alox5 regulation of LSC function by focusing on two downstream genes Msr1 and beta-catenin; and to study whether the regulation of the Alox5 pathway affects the function of human CML stem cells. The knowledge learned from studying LSCs will also help to understand cancer stem cells in other types of malignant diseases.

慢性髓细胞白血病（CML）是最常见的骨髓增殖功能障碍症，本项目旨在确定CML中干细胞的决定性基因及其功能，了解相关分子网络，最终建立高效靶向治疗CML的策略。为此，我们建立了BCR-ABL癌基因诱导人CML的小鼠模型。现有的CML药物具有使用时相限制、易产生耐药性的缺点，为了开发适宜的CML化疗药物，需了解LSCs的关键基因及其内在机制。CML是干细胞疾病，它的生存和自我更新机制与正常干细胞不同，需要花生四烯酸5-脂加氧酶(5-LO)基因(Alox5)。 Alox5是LSCs中主要的分子通路，调控了两组基因构成的分子网络，彻底了解它如何作用于其下游基因，可以靶向追踪LSCs。实验目标主要有验证Alox5基因是否通过白三烯调节LSCs的功能；研究Alox5下游基因Msr1和β-catenin对LSCs的调控机制；研究Alox5能否调控人CML干细胞。相关成果可应用于其他恶性血液病的治疗。

慢性髓系白血病（CML）是最常见的骨髓增殖功能障碍症，本项目旨在确定CML中干细胞的决定性基因及其功能，了解相关分子网絡，最后建立高效靶向治疗CML的策略。因此，我们建立了BCR-ABL癌基因誘导人CML的小鼠模型。现有的CML药物具有使用时相限制、易产生耐药性的缺点，为了开发适宜的CML化疗药物，需了解LSCs的关键基因及其内在机制。CML是干细胞疾病，它的生存和自我更新机制与正常干细胞不同，需要花生四烯酸5-脂加氧酶(5-LO)基因(Alox5)。 Alox5是LSCs中主要的分子通路，调控了两组基因构成的分子网絡，彻底了解它如何作用于其下游基因，可以靶向追踪LSCs。实验目标主要有验证Alox5基因是否通过白三烯调解LSCs的功能；研究Alox5下游基因Msr1和β-catenin对LSCs的调控机制；研究Alox5能否调控人CML干细胞。相关成果可应用于其他恶性血液病的治疗。