Mitochondrial Dysfunction underlies treatment related hepatotoxicity in Hispanics with acute lymphoblastic leukemia

项目标题：线粒体功能障碍是治疗与肝毒性有关的拉美裔人的基础 急性淋巴细胞性白血病 摘要： 急性淋巴细胞白血病是儿童最常见的癌症类型，在中国发病率较高 西班牙裔。虽然儿童急性淋巴细胞性白血病(ALL)的总体存活率已达到约 90%，成人ALL患者的预后仍然很差(45%)。西班牙裔儿童、青少年和青年 成人(阿雅)也都遭受较差的结果。天冬酰胺酶在儿科治疗方案中的密集使用 提高了儿童的治愈率，但成人天冬酰胺酶相关毒性的较高发生率限制了其 在这个年龄段广泛使用。肝毒性是一种特别重要的药物引起的禁忌症，因为 目前的建议是，当出现3级或4级肝毒性时，不使用天冬酰胺酶治疗。 这发生在大约30%的患者中，可能会影响其治疗效果。西班牙裔患者 与其他种族相比，发生肝毒性的比率更高。肥胖和/或年龄较大的儿童 尤其是有肝脏毒性的风险。不幸的是，对ALL中天冬酰胺酶的药物基因组学研究有限。 而且主要集中在高加索儿童患者身上。在以非西班牙裔为主的人口中，我们以前 报道了SOD2中的遗传变异rs4880，它编码了一种关键的线粒体酶，可以保护人们免受 在成人ALL患者中，活性氧物种(ROS)与天冬酰胺酶诱导的肝毒性有关。 高危CC基因在西班牙裔人群中更为常见，他们也表现出更高的患病率 ALL和天冬酰胺酶引起的肝毒性高于其他种族。在以西班牙裔为主的143名儿科医生队列中 接受了天冬酰胺酶方案的ALL患者，我们发现肝酶升高更高 用天冬酰胺酶治疗后的拉美裔美国人比非西班牙裔美国人。Rs4880 CC基因型显著高于对照组。 在西班牙裔中也更常见，并与天冬酰胺酶治疗后肝酶升高有关 西班牙裔患者的体重指数更高，这一点也更高。总而言之，这些数据表明 氧化应激病因学涉及广泛的代谢紊乱，导致与以下相关的肝脏毒性 门冬酰胺酶在急性淋巴细胞白血病患者中的表达。在这里，我们建议探索线粒体酶和 拉美裔美国人线粒体功能障碍和天冬酰胺酶所致的肝毒性。我们假设 线粒体功能障碍和氧化应激参与门冬酰胺酶诱导的大鼠肝毒性 西班牙裔。我们的目标是：目标1)确定线粒体中的遗传和代谢变化 对天门冬酰胺酶引起的拉美裔人的肝毒性。目标2)开发一个计算模型来预测 门冬酰胺酶在西班牙裔急性淋巴细胞白血病患者中引起的肝毒性。 我们的研究将提供线粒体功能障碍和线粒体功能障碍之间联系的功能证据。 天冬酰胺酶与拉美裔人的肝毒性相关，为临床预测天冬酰胺酶提供了有用的工具。 西班牙裔急性淋巴细胞白血病患者的肝毒性。更广泛地说，我们的发现将揭示机械论的见解 需要开发降低毒性和提高急性淋巴细胞白血病患者疗效的疗法。

PROJECT TITLE: Mitochondrial dysfunction underlies treatment related hepatotoxicity in Hispanics with acute lymphoblastic leukemia ABSTRACT: Acute Lymphoblastic leukemia is the most common type of cancer in children with higher prevalence in Hispanics. While overall survival for children with acute lymphoblastic leukemia (ALL) has reached approximately 90%, the outcome for adult patients with ALL remains poor (<45%). Hispanic children and adolescent and young adult (AYA) both also suffer inferior outcomes. The intensive use of asparaginase in pediatric regimens has enhanced the cure rate of children, but the higher rate of asparaginase-related toxicity in adults has limited its widespread use in this age group. Hepatotoxicity is a particularly important drug-induced contraindication, as current recommendations of withholding asparaginase treatment when grade 3 or 4 hepatotoxicity develops, which occurs in approximately 30% of ALL patients, may compromise its therapeutic effect. Hispanic patients developed hepatotoxicity at an increased rate compared with other ethnicities. Obese and/or older children are particularly at risk for hepatotoxicity. Unfortunately, pharmacogenomic studies of asparaginase in ALL are limited and mostly focus on Caucasian pediatric patients. In a predominantly non-Hispanic population, we previously reported that genetic variant rs4880 in SOD2, which encodes a key mitochondrial enzyme protective against reactive oxygen species (ROS), is associated with asparaginase-induced hepatotoxicity in adult ALL patients. The high-risk CC genotype is more common in Hispanic individuals, who also exhibit a greater prevalence of ALL and asparaginase-induced hepatotoxicity than other ethnicities. In a largely Hispanics cohort of 143 pediatric patients with ALL who have received asparaginase based regimen, we found higher elevation of liver enzymes post treatment with asparaginase in Hispanics than non-Hispanics. The rs4880 CC genotype was significantly also more frequent in Hispanics and was associated with elevated liver enzymes post asparaginase treatment and higher body mass index which was also higher is Hispanic patients. Altogether, these data suggest an oxidative stress etiology involved in a wide range of metabolic disorders leading to liver toxicities associated with asparaginase in patients with ALL. Here we propose to explore the link between the mitochondrial enzymes and mitochondrial dysfunction and asparaginase induced hepatotoxicity in Hispanics. We hypothesize that mitochondrial dysfunction and oxidative stress contribute to asparaginase-induced hepatotoxicity in Hispanics. Our aims are: Aim 1) Identify genetic and metabolic alterations in the mitochondria that contribute to asparaginase-induced hepatotoxicity in Hispanics. Aim 2) Develop a computational model to predict asparaginase-induced hepatotoxicity in Hispanic patients with ALL. Our study will provide functional evidence of the association between the mitochondrial dysfunction and asparaginase related hepatotoxicity in Hispanics and provide clinically useful tool for predicting asparaginase- induced hepatotoxicity in Hispanic patients with ALL. More broadly, our findings will reveal mechanistic insights needed to develop therapies with reduced toxicity and improved efficacy in patients with ALL.