Investigating the Role of Adipocytes on Leukemia Relapse

肥胖会增加多种癌症的发病率和死亡率。最近的一次回顾 研究发现，确诊时肥胖的儿童是高危急性淋巴细胞白血病 (ALL)与瘦孩子相比，复发的风险增加了50%。较高的死亡率可能是由于 肥胖对白血病本身的直接影响，可能是通过某些脂肪细胞衍生的激素或 细胞因子。或者，这可能是肥胖的影响，混淆了白血病的治疗，可能是由于 化疗药物的药代动力学改变。鉴于ALL和肥胖症的高患病率，它是 我们必须调查这两种情况之间的联系。因此，我们开发了小鼠 肥胖症和所有人的模型。我们发现，患有急性淋巴细胞白血病的肥胖小鼠在治疗后更有可能复发 使用长春新碱，即使剂量与体重成比例。此外，我们有体外数据显示 脂肪细胞对ALL化疗有多种影响：它们分泌尚不确定的因素 引起对地塞米松的所有抵抗，并将长春新碱浓缩到细胞外 环境，使得所有细胞都无法访问。 本研究旨在以这些结果为基础。在我们的第一个目标中，我们将使用蛋白质组学 鉴定导致地塞米松耐药的脂肪细胞衍生因子(S)的方法。我们会 探讨其合成分泌的调节作用及作用机制(S)。 细胞。在我们的第二个目标中，我们将在肥胖小鼠身上进行长春新碱和长春新碱的药代动力学实验。 地塞米松来量化肥胖如何改变白血病对这些制剂的暴露。最后，在第三个目标中， 我们将在免疫抑制的小鼠中使用一种新的饮食诱导肥胖模型，NOD/SCID IL2R？c-/- 小鼠，探讨肥胖对体内人白血病细胞的影响。在这种模式下，我们还将 研究白血病如何渗入脂肪组织可能导致对治疗的抵抗。 这些研究将增加我们对白血病及其与肥胖的关系的了解，它们具有 在我们日益超重的人口中，有可能改变我们治疗癌症的方式。他们还将提供 洞察白血病细胞的生态位，并确定所有糖皮质激素耐药的潜在靶点。这些 研究可以直接导致癌症治疗的改进，并挽救瘦身和超重患者的生命 无论是孩子还是成年人。

Obesity increases both the incidence and mortality of numerous types of cancer. A recent retrospective study found that children who are obese at the time of diagnosis of high-risk acute lymphoblastic leukemia (ALL) have a 50% increased risk of relapse compared to lean children. This higher mortality may be due to a direct effect of obesity on the leukemia itself, perhaps mediated by some adipocyte-derived hormone or cytokine. Alternatively, it may be an effect of obesity to confound the leukemia treatment, possibly due to altered pharmacokinetics of chemotherapeutic agents. Given the high prevalence of both ALL and obesity, it is imperative that we investigate the link between these two conditions. Therefore, we have developed mouse models of obesity and ALL. We have found that obese mice with ALL are more likely to relapse after treatment with vincristine, even when it is dosed proportional to body weight. Also, we have in vitro data demonstrating that adipocytes have multiple effects to impair chemotherapy of ALL: they secrete as yet unidentified factors which cause ALL resistance to dexamethasone, and they concentrate vincristine out of the extracellular environment, making it inaccessible to the ALL cells. The present studies are designed to build on these results. In our first Aim, we will use a proteomics approach to identify the adipocyte-derived factor(s) responsible for causing dexamethasone resistance. We will also investigate the regulation of their synthesis and secretion, and their mechanism(s) of action on leukemia cells. In our second Aim, we will perform pharmacokinetics experiments in obese mice with vincristine and dexamethasone to quantify how obesity alters the leukemia exposure to these agents. Finally, in our third Aim, we will use a novel model of diet-induced obesity in an immunosuppressed mouse, the NOD/SCID IL2R ¿c -/- mouse, to explore the effects of obesity on human leukemia cells in vivo. With this model we will also investigate how leukemia infiltration into adipose tissue may lead to resistance to therapy. These studies will increase our understanding of leukemia and its relation to obesity, and they have the potential to change the way we treat cancer in our increasingly overweight population. They will also provide insight into the leukemia cell niche and identify potential targets for ALL glucocorticoid resistance. These studies could lead directly to improvements in cancer treatment and saved lives in both lean and overweight children and adults.