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

项目名称：线粒体功能障碍是西班牙裔患者治疗相关肝毒性的基础， 急性淋巴细胞白血病 摘要： 急性淋巴细胞白血病是儿童中最常见的癌症类型， 西班牙裔虽然儿童急性淋巴细胞白血病（ALL）的总生存率已达到约 90%，成人ALL患者的结局仍然较差（<45%）。西班牙裔儿童和青少年 成人（AYA）也遭受较差的结果。门冬酰胺酶在儿科治疗方案中的大量使用， 提高了儿童的治愈率，但成人天冬酰胺酶相关毒性的发生率较高，限制了其 在这个年龄段广泛使用。肝毒性是一个特别重要的药物引起的禁忌症， 目前的建议是当发生3级或4级肝毒性时停止天冬酰胺酶治疗， 这发生在大约30%的ALL患者中，可能会损害其治疗效果。西班牙裔患者 与其他种族相比，肝毒性发生率增加。肥胖和/或年龄较大的儿童 特别是有肝毒性的风险。不幸的是，天冬酰胺酶在ALL中的药物基因组学研究有限 主要集中在白人儿科患者身上在一个主要的非西班牙裔人口，我们以前 报道了SOD 2中的遗传变异rs 4880，它编码一种关键的线粒体酶， 活性氧簇（ROS）与成人ALL患者中天冬酰胺酶诱导的肝毒性相关。 高风险CC基因型在西班牙裔个体中更常见，他们也表现出更高的患病率， ALL和天冬酰胺酶诱导的肝毒性高于其他种族。在一个由143名儿童组成的以西班牙裔为主的队列中， 接受以门冬酰胺酶为基础的治疗方案的ALL患者，我们发现肝酶升高更高， 西班牙裔患者在天冬酰胺酶治疗后比非西班牙裔患者更明显。rs 4880 CC基因型与对照组相比，差异有统计学意义（P <0.05）。 在西班牙裔中也更常见，并与天冬酰胺酶治疗后肝酶升高相关 西班牙裔患者的体重指数也更高。总之，这些数据表明， 氧化应激病因学涉及广泛的代谢紊乱，导致肝毒性， 急性淋巴细胞白血病患者的门冬酰胺酶。在这里，我们建议探索线粒体酶和 线粒体功能障碍和天冬酰胺酶诱导的肝毒性。我们假设 线粒体功能障碍和氧化应激导致天冬酰胺酶诱导的肝毒性， 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改变， 天冬酰胺酶诱导的西班牙裔肝毒性。目标2）开发一个计算模型来预测 西班牙裔ALL患者中天冬酰胺酶诱导的肝毒性 我们的研究将为线粒体功能障碍与 西班牙裔人中天冬酰胺酶相关肝毒性，并为预测天冬酰胺酶- 在西班牙裔ALL患者中诱导肝毒性。更广泛地说，我们的发现将揭示机械的见解， 需要开发降低毒性和提高ALL患者疗效的治疗方法。

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.