Faculty, Staff and Student Publications
Publication Date
5-1-2024
Journal
Nature Communications
Abstract
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.
Keywords
Humans, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Pharmacogenetics, Child, Drug Resistance, Neoplasm, Genetic Variation, Cell Line, Tumor, Vincristine, Polymorphism, Single Nucleotide, Alleles, Chromatin, Trans-Activators, Antineoplastic Agents, Gene Expression Regulation, Leukemic, Proto-Oncogene Proteins
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Medical Sciences Commons, Oncology Commons
Comments
Supplementary Materials
PMID: 38693155