白血病干细胞生存和干性维持的关键信号通路

Human Philadelphia chromosome-positive chronic myeloid leukemia (CML) induced by the BCR-ABL oncogene is a stem cell disease, serving as an excellent model disease for studying the biology and molecular signaling of cancer stem cells. An anti- leukemia stem cell (LSC) strategy needs to be developed for curing the disease. In this application, we aim to identify novel signaling genes critically required for functional regulation of LSCs basing on our preliminary results showing that the arachidonate 12/15-lipoxygenase gene, which produces lipid metabolites from arachidonic acid, is required for maintaining LSC function and essential for CML development. Specifically, in the absence of 12/15-lipoxygenase gene, LSC function is lost and BCR-ABL fails to induce CML.12/15-lipoxygenase gene represents a major molecular pathway critically required for LSC function, and it will be crucial to fully understand how 12/15-lipoxygenase gene signals to other downstream signaling molecules in LSCs and to test whether 12/15-lipoxygenase gene is a good target gene in human CML stem cells. The specific aims are: 1) To study whether 12/15-lipoxygenase gene regulates LSC function through its lipid metabolites; 2) To study the molecular mechanisms by which 12/15-lipoxygenase gene regulates LSC function; and 3) To study whether alteration of 12/15-lipoxygenase gene activity affects the function of human CML stem cells. The knowledge learned from studying 12/15-lipoxygenase gene in functional regulation of LSCs in CML will also have a significant impact on our understanding of cancer stem cells in other types of cancer..

由BCR-ABL癌基因引发的人类费城染色体阳性慢性髓系白血病（CML）源于白血病干细胞，12/15脂氧合酶基因受药物抑制或敲除时，LSC的功能缺失，BCR-ABL无法诱导CML。12/15脂氧合酶基因是维持 LSC功能的代表性基因，本项目旨在完全了解它如何调控LSC中各种下游信号分子，进而判定它能否作为清除人类CML干细胞的靶基因。本项目的研究目标是从12/15脂氧合酶基因的代谢物入手，从不同的下游基因展开验证12/15脂氧合酶基因能否决定性地调控LSCs，确定12/15脂氧合酶基因是否通过其脂类代谢物调控LSC功能；阐明12/15脂氧合酶基因调控LSC功能的分子机制；研究12/15脂氧合酶基因对人类CML干细胞的影响等。

由BCR-ABL癌基因引发的人类费城染色体阳性慢性髓系白血病（CML）源于白血病干细胞 （leukemia stem cell, LSC），12/15脂氧合酶基因受药物抑制或敲除时，LSC的功能缺失，BCR-ABL无法诱导CML。12/15脂氧合酶基因是维持 LSC功能的代表性基因，本项目旨在完全了解它如何调控LSC中各种下游信号分子，进而判定它能否作为清除人类CML干细胞的靶基因。本项目的研究目标是从12/15脂氧合酶基因的代谢物入手，从不同的下游基因展开验证12/15脂氧合酶基因能否决定性地调控LSCs，确定12/15脂氧合酶基因是否通过其脂类代谢物调控LSC功能；阐明12/15脂氧合酶基因调控LSC功能的分子机制；研究12/15脂氧合酶基因对人类CML干细胞的影响等。研究结果表明：1）12/15-脂氧合酶基因是通过代谢花生四烯酸产生脂类代谢物来调控慢性髓系白血病LSC； 2）c-Myc与12/15-脂氧合酶和P-selectin有功能上的联系； and 3）12/15-脂氧合酶调控PV LSC的功能。