Novel targeted therapy to reduce health disparities in pediatric leukemia

摘要 西班牙裔/拉丁裔（H/L）儿童和青少年的死亡率比非西班牙裔白人（NHW）高40% 修正社会经济因素后最近，我们发现了一个高度增加的发生率缺失的一个 IKZF 1等位基因在H/L儿童中的表达，为B细胞急性白血病预后不良提供了生物学依据。 淋巴细胞白血病（B-ALL）。非常高的发生率（29%）使得一个缺失 IKZF 1等位基因是H/L儿童B-ALL中最常见的遗传变异，可导致不良预后。因此，在本发明中， 了解化疗耐药的生物学基础，开发治疗B-ALL的新疗法 一个IKZF 1等位基因的缺失将减少西班牙裔/拉丁裔ALL儿童生存期的健康差异。 IKZF 1基因编码一种DNA结合蛋白IKAROS，其作为转录调节因子发挥作用。我们 已发表的数据显示，在B-ALL中，IKAROS被致癌酪蛋白激酶II（CK 2）磷酸化， 降低IKAROS DNA结合亲和力并消除其作为转录调节因子的功能。我们的新 初步数据表明，CK 2削弱IKAROS抑制两个关键基因转录的能力 参与硫嘌呤途径，对6-巯基嘌呤（6-MP）治疗的耐药性和复发：TPMT和 NT5C2。用CK 2特异性抑制剂CX-4945治疗恢复IKAROS介导的TPMT抑制 和NT 5C 2基因。在体外用CX-4945治疗B-ALL， 与6-MP组合显示出强的协同细胞毒作用。我们的总体假设是 高风险B-ALL的H/L儿童中CK 2的过度表达损害IKAROS转录抑制 调节对6-MP治疗的抗性的基因，并且CK 2抑制将恢复IKAROS功能， 这些基因的转录抑制因子，导致对6-MP的敏感性增加。这一假设将是 使用各种生物模型进行体内测试。我们将定义IKAROS调节的机制 H/L儿童原发性B-ALL细胞中的硫嘌呤途径。CK 2表达增加对 硫嘌呤途径和IKAROS功能将在患者来源的异种移植物（PDX）中进行分析， B-ALL来自H/L儿童。最后，我们将确定与CK 2联合治疗的疗效。 抑制剂（CX-4945）和6-巯基嘌呤（6-MP）在H/L儿童B-ALL临床前模型中的作用。结果 该项目将提供一个新的洞察硫嘌呤途径的调节，并帮助开发新的 治疗H/L儿童中的高危B-ALL，并减少儿童癌症健康差异。

ABSTRACT Hispanic/Latino (H/L) children and adolescents have a 40% higher death rate than non-Hispanic whites (NHW) after correcting socioeconomic factors. Recently, we identified a highly increased incidence of deletion of one IKZF1 allele in H/L children, which provided a biological rationale for the worse prognosis of B-cell acute lymphoblastic leukemia (B-ALL) in this population. The very high incidence (29%) makes the deletion of one IKZF1 allele the most frequent genetic alteration that confers adverse prognosis in B-ALL in H/L children. Thus, understanding the biological basis for resistance to chemotherapy and developing novel therapies to treat B-ALL with deletion of one IKZF1 allele will reduce the health disparity in survival for Hispanic/Latino children with ALL. The IKZF1 gene encodes a DNA-binding protein, IKAROS, which functions as a transcriptional regulator. Our published data showed that, in B-ALL, IKAROS phosphorylation by the oncogenic Casein Kinase II (CK2) reduces IKAROS DNA-binding affinity and abolishes its function as a transcriptional regulator. Our new preliminary data suggest that CK2 impairs the ability of IKAROS to repress transcription of two key genes involved in the thiopurine pathway, resistance to 6-mercaptopurine (6-MP) treatment, and relapse: TPMT and NT5C2. Treatment with CK2-specific inhibitor, CX-4945, restores IKAROS-mediated repression of the TPMT and NT5C2 genes in primary B-ALL cells from H/L children. In vitro treatment of B-ALL with CX-4945 in combination with 6-MP exhibits a strong synergistic cytotoxic effect. Our overall hypothesis is that overexpression of CK2 in high-risk B-ALL of H/L children impairs IKAROS’ ability to transcriptionally repress the genes that regulate resistance to treatment with 6-MP, and that CK2 inhibition will restore IKAROS function as a transcriptional repressor of these genes, resulting in increased sensitivity to 6-MP. This hypothesis will be tested in vivo, using various biological models. We will define the mechanism through which IKAROS regulates the thiopurine pathway in primary B-ALL cells from H/L children. The effect of increased CK2 expression on thiopurine pathway and IKAROS function will be analyzed in patient-derived xenografts (PDXs), generated from B-ALL from H/L children. Finally, we will establish the therapeutic efficacy of combination treatment with CK2 inhibitor (CX-4945) and 6-mercaptopurine (6-MP) in a preclinical model of B-ALL from H/L children. Results of the project will provide a novel insight into the regulation of the thiopurine pathway and help develop novel treatments for high-risk B-ALL in H/L children and reduce childhood cancer health disparities.