Targeting Leukemia Stem Cells with Dietary Selenium

描述（由申请人提供）：硒（Se）作为硒代半胱氨酸掺入硒蛋白中，以赋予抗癌、抗氧化和抗炎功能。基于我们正在进行的研究，在轻微高Se状态下，免疫细胞将花生四烯酸代谢转向产生环氧合酶（考克斯）衍生的抗炎性环戊烯酮前列腺素（CyPG）15 d-PGJ 2，而不是促炎性PGE 2和血栓烷A2.许多研究表明，高硒抑制乳腺癌、结肠癌和前列腺癌的啮齿动物模型的起始、促进和进展，其中大量癌细胞的凋亡增强。然而，研究还有待于了解硒对癌症干细胞（CSC）的影响，CSC占据了发展层次的顶点，具有自我更新，多能性和强大的增殖能力。治疗癌症的现有疗法不能根除CSC，因此有助于许多癌症的复发。为了填补这一普遍存在的空白，我们建议在以下三种模型中研究膳食硒对白血病干细胞（LSC）增殖的影响：1）分别作为慢性骨髓性白血病（CML）和AML模型，移植来自移植有表达融合癌蛋白BCR-ABL或MLL-AF 9的造血干细胞（HSC）的C57 BL/6小鼠的Sca 1 +kit+GFP+ LSC，（2）M34+ Sca 1 +kit+ LSC，来自Friend白血病逆转录病毒感染的Balb/c小鼠--红细胞增多症，一种急性髓细胞性白血病（AML）模型。基于考克斯抑制剂阻断体内白血病硒依赖性消融作用的令人信服的初步数据，我们假设超生理水平的膳食硒增加内源性CyPG的产生，通过激活p53途径特异性靶向LSC凋亡。该假设将在三个特定目的中进行检验：1）检查高Se补充是否导致LSC消融; 2）检查考克斯途径代谢物在Se补充小鼠中选择性靶向LSC中的作用; 3）描述Se补充小鼠中15 d-PGJ 2诱导LSC凋亡的机制。鉴于白血病患者血清硒水平降低以及服用非阿司匹林止痛药的成人白血病发病率较高的流行病学证据，我们的长期目标是了解白血病患者补充硒是否有益。 公共卫生相关性：这项提议是基于硒生物学中一个研究相对不足的领域，该领域研究了这种微量营养素在选择性根除白血病干细胞中的作用。在补硒条件下，内源性前列腺素代谢物的形成及其在根除白血病干细胞中的作用将在三种良好建立的小鼠模型中使用白血病干细胞移植和白血病消融进行研究。

DESCRIPTION (provided by applicant): Selenium (Se) is incorporated into selenoproteins as selenocysteine to impart anti-cancer, antioxidant, and anti-inflammatory functions. Based on our ongoing studies, under marginally high Se status, immune cells shunt the arachidonic acid metabolism towards the production of cyclooxygenase (COX)-derived anti-inflammatory cyclopentenone prostaglandin (CyPG) 15d- PGJ2 rather than pro-inflammatory PGE2 and thromboxane A2. Many studies have shown that high Se inhibits the initiation, promotion, and progression in rodent models of breast, colon, and prostate cancer, where apoptosis of bulk cancer cells was enhanced. However, studies are yet to be done to understand the effect of Se on cancer stem cells (CSC), which occupy the apex of the developmental hierarchy with properties of self-renewal, multipotentiality, and strong proliferative capacity. Existing therapie to treat cancer do not eradicate the CSCs and thus, aid in the relapse of many cancers. To fill this pervasive gap, we propose to examine the effect of dietary Se on the proliferation of leukemia stem cells (LSC) in the following three models: 1) transplantation of Sca1+kit+GFP+LSCs from C57BL/6 mice transplanted with hematopoietic stem cells (HSC) that express the fusion oncoproteins BCR-ABL or MLL-AF9 as models of chronic myelogenous leukemia (CML) and AML, respectively, and 2) M34+Sca1+kit+ LSCs from Balb/c mice infected with Friend leukemia retrovirus-polycythemia, a model of acute myelogenous leukemia (AML). Based on the compelling preliminary data that COX inhibitors block the effect of Se-dependent ablation of leukemia in-vivo, we hypothesize that supraphysiological levels of dietary Se increases the production of endogenous CyPGs to specifically target LSCs to apoptosis by activating the p53 pathway. The hypothesis will be tested in three Specific Aims: 1) To examine if high Se supplementation causes the ablation of LSCs; 2) To examine the role of COX pathway metabolites in the selective targeting of LSCs in Se-supplemented mice, and 3) To delineate the mechanism of apoptosis of LSCs by 15d-PGJ2 in Se supplemented mice. Given the epidemiological evidence of lowered serum Se levels in leukemia patients as well as higher incidences of adult leukemia in individuals consuming non-aspirin analgesics, our long- term goal is to understand if Se supplementation of leukemia patients would be beneficial. PUBLIC HEALTH RELEVANCE: The proposal is based on a relatively understudied area in selenium biology that examines the role of this micronutrient in the selective eradication of leukemia stem cells. Under selenium supplemented conditions, the formation of endogenous prostaglandin metabolites and their role in the eradication of leukemia stem cells will be studied using transplantation of leukemia stem cells and ablation of leukemia in three well established murine models.