Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
Nat Commun. 2024 May 1;15(1):3681. doi: 10.1038/s41467-024-48124-4.
Defining genetic factors impacting chemotherapy failure can help to better predict response and identify drug resistance mechanisms. However, there is limited understanding of the contribution of inherited noncoding genetic variation on inter-individual differences in chemotherapy response in childhood acute lymphoblastic leukemia (ALL). Here we map inherited noncoding variants associated with treatment outcome and/or chemotherapeutic drug resistance to ALL cis-regulatory elements and investigate their gene regulatory potential and target gene connectivity using massively parallel reporter assays and three-dimensional chromatin looping assays, respectively. We identify 54 variants with transcriptional effects and high-confidence gene connectivity. Additionally, functional interrogation of the top variant, rs1247117, reveals changes in chromatin accessibility, PU.1 binding affinity and gene expression, and deletion of the genomic interval containing rs1247117 sensitizes cells to vincristine. Together, these data demonstrate that noncoding regulatory variants associated with diverse pharmacological traits harbor significant effects on allele-specific transcriptional activity and impact sensitivity to antileukemic agents.
确定影响化疗失败的遗传因素有助于更好地预测反应并识别耐药机制。然而，对于遗传非编码遗传变异对儿童急性淋巴细胞白血病 (ALL) 化疗反应个体间差异的贡献，我们的了解有限。在这里，我们将与治疗结果和/或化疗耐药性相关的遗传非编码变体映射到 ALL 顺式调控元件，并分别使用大规模平行报告基因检测和三维染色质环化检测来研究它们的基因调控潜力和靶基因连通性。我们确定了 54 个具有转录效应和高置信度基因连通性的变体。此外，对顶级变体 rs1247117 的功能研究揭示了染色质可及性、PU.1 结合亲和力和基因表达的变化，并且包含 rs1247117 的基因组间隔缺失使细胞对长春新碱敏感。总之，这些数据表明，与多种药理学特征相关的非编码调节变体对等位基因特异性转录活性具有显著影响，并影响对抗白血病药物的敏感性。
