Evaluation of myocardial targets to prevent anthracycline cardiotoxicity in children with Down Syndrome and Leukemia

患有唐氏综合症（DS，21三体）的儿童患某些癌症的风险增加。儿童 据报道，DS发生急性髓性白血病（AML）的风险增加10-20倍。蒽环 治疗方案在患有DS和AML的儿科患者中取得了良好的结果。然而，患有AML的儿童 和DS具有治疗相关毒性的高风险，包括蒽环类药物相关的心脏毒性。为 例如，儿童肿瘤组的一份报告记录了蒽环类药物相关的心肌病， 17.5%的AML和DS患者。就对以下疾病的易感性而言，个体间差异很大： 蒽环类药物相关的心脏毒性，并且没有临床治疗方法来预防 AML和DS儿童的心脏毒性。在过去的八年里，我们一直在进行综合研究 确定与个体蒽环类药物心脏毒性发病机制相关的心肌决定因素 在DS我们已经证明，21号染色体基因CBR 1的表达增加，在DS心肌 并导致心脏毒性蒽环类醇代谢物的较高合成速率。这很重要因为 高CBR 1活性产生的蒽环类醇代谢物的心脏毒性是母体的40倍 蒽环类这些发现有助于支持新的剂量减少策略的基本原理， 儿童肿瘤组实施的临床方案（试验：AAML 0431. Blood，2017）.小说 初步数据表明，DYRK 1A（与多种疾病相关的21号染色体关键基因）的表达 DS表型在DS心肌中改变。我们的数据还表明，1）胚胎的表达， 心肌肌钙蛋白TNNT 2的转录变体和2）主剪接因子SRp 55显著增加 在DS患者的心肌组织中。我们认为DYRK 1A-SRp 55- TNNT 2通路增加了DS心肌对蒽环类药物心脏毒性作用的敏感性。 目的1中的研究将检查DYRK 1A-SRp 55-TNNT 2途径在蒽环类药物心脏毒性中的作用 在一个跳动的21三体心肌细胞模型中。目标2中的研究将检查是否结合 CBR 1和DYRK 1A活性的药理学抑制保护三体心肌细胞免受心脏毒性 抗癌蒽环类药物的作用。为了进一步研究DS中药物诱导的心脏毒性的决定因素， 目标3中的研究将确定与以下表达增加相关的全基因组剪接改变的程度： DS患者心肌组织中的主要剪接因子SRp 55。这些综合研究将 为预防蒽环类药物发展的药物干预设计提供新数据 儿童DS和AML患者的心脏毒性。

Children with Down syndrome (DS, trisomy 21) are at increased risk of developing certain cancers. Children with DS have a reported 10-20 fold increased risk of developing acute myeloid leukemia (AML). Anthracycline-based treatment regimens achieve good results in pediatric patients with DS and AML. However, children with AML and DS are at high risk for treatment-related toxicities, including anthracycline-related cardiotoxicity. For example, a report from the Children's Oncology Group documented anthracycline-related cardiomyopathy in 17.5 % of the patients with AML and DS. There is wide inter-individual variability in terms of susceptibility to anthracycline-related cardiotoxicity, and there are no clinical treatments to prevent the development of cardiotoxicity in children with AML and DS. For the past eight years, we have been conducting integrative studies to identify myocardial determinants associated with the pathogenesis of anthracycline cardiotoxicity in individuals with DS. We have shown that the expression of the chromosome 21 gene CBR1 is increased in DS myocardium and results in higher synthesis rates of cardiotoxic anthracycline alcohol metabolites. This is important because anthracycline alcohol metabolites resulting from high CBR1 activity are 40 times more cardiotoxic than parent anthracyclines. These findings have contributed to support the rationale for dose reduction strategies in new clinical protocols implemented by the Children's Oncology Group (trial: AAML0431. Blood, 2017). Novel preliminary data suggest that the expression of DYRK1A, a key chromosome 21 gene associated with various DS phenotypes, is altered in DS myocardium. Our data also suggest that the expressions of 1) embryonic transcript variants of cardiac troponin TNNT2 and 2) the master splicing factor SRp55, are significantly increased in myocardial tissue from individuals with DS. We propose that altered expression of the DYRK1A-SRp55- TNNT2 pathway increases the susceptibility of DS myocardium to the cardiotoxic effects of anthracycline drugs. Studies in Aim 1 will examine the role of the DYRK1A-SRp55-TNNT2 pathway during anthracycline cardiotoxicity in a model of beating cardiomyocytes with trisomy 21. Studies in Aim 2 will examine whether combined pharmacological inhibition of CBR1 and DYRK1A activities protects trisomic cardiomyocytes from the cardiotoxic effects of anticancer anthracyclines. To further investigate determinants for drug induced cardiotoxicity in DS, studies in Aim 3 will define the extent of genome-wide splicing alterations linked to the increased expression of the master splicing factor SRp55 in myocardial tissue from persons with DS. These integrative studies will provide new data for the design of pharmacological interventions to prevent the development of anthracycline cardiotoxicity in pediatric patients with DS and AML.