Investigating the Role of Adipocytes on Leukemia Relapse

肥胖增加了许多类型癌症的发病率和死亡率。最近的一项回顾性 研究发现，在诊断为高危急性淋巴细胞白血病时肥胖的儿童 (ALL)与瘦的孩子相比，复发的风险增加了50%。这种高死亡率可能是由于 肥胖对白血病本身的直接影响，可能是由一些脂肪细胞衍生的激素或 细胞因子或者，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和肥胖的高患病率， 我们必须调查这两种情况之间的联系。因此，我们开发了鼠标 肥胖和ALL的模型。我们发现患有ALL的肥胖小鼠在治疗后更容易复发 长春新碱，即使剂量与体重成比例。同时，我们有体外实验数据证明 脂肪细胞对急性淋巴细胞白血病的化疗有多种影响：它们分泌尚未鉴定的因子， 导致ALL对地塞米松产生耐药性，并将长春新碱从细胞外 环境，使其无法进入所有细胞。 本研究旨在建立在这些结果的基础上。在我们的第一个目标中，我们将使用蛋白质组学 一种鉴定导致地塞米松抵抗的脂肪细胞衍生因子的方法。我们将 并研究其合成和分泌的调节及其对白血病的作用机制 细胞在我们的第二个目标中，我们将在肥胖小鼠中进行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暴露于这些药物。最后，在第三个目标中， 我们将在免疫抑制小鼠中使用一种新的饮食诱导肥胖模型，NOD/SCID IL 2 R c -/- 小鼠，探讨肥胖对体内人白血病细胞的影响。通过这种模式，我们还将 研究白血病浸润到脂肪组织中如何导致对治疗的抵抗。 这些研究将增加我们对白血病及其与肥胖关系的理解， 有可能改变我们在日益超重的人群中治疗癌症的方式。他们还将提供 深入了解白血病细胞生态位并识别ALL糖皮质激素耐药的潜在靶点。这些 这些研究可能会直接改善癌症治疗，并挽救瘦人和超重者的生命。 儿童和成人。

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.