{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"submitter":["Bhattarai KR"],"funding":["NCI NIH HHS","NIGMS NIH HHS"],"pubmed_abstract":["Although acute lymphoblastic leukemia (ALL) is the most common childhood cancer, there is limited understanding of the contribution of inherited genetic variation on inter-individual differences in chemotherapy response. Defining genetic factors impacting therapy failure can help better predict response and identify drug resistance mechanisms. We therefore mapped inherited noncoding variants associated with chemotherapeutic drug resistance and/or treatment outcome to ALL <i>cis</i>-regulatory elements and investigated their gene regulatory potential and genomic connectivity using massively parallel reporter assays and promoter capture Hi-C, respectively. We identified 53 variants with reproducible allele-specific effects on transcription and high-confidence gene targets. Subsequent functional interrogation of the top variant (rs1247117) determined that it disrupted a PU.1 consensus motif and PU.1 binding affinity. Importantly, deletion of the genomic interval containing rs1247117 sensitized ALL cells to vincristine. Together, these data demonstrate that noncoding regulatory variation associated with diverse pharmacological traits harbor significant effects on allele-specific transcriptional activity and impact sensitivity to chemotherapeutic agents in ALL."],"journal":["medRxiv : the preprint server for health sciences"],"pagination":["2023.02.10.23285762"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC9934807"],"repository":["biostudies-literature"],"pubmed_title":["Functional investigation of inherited noncoding genetic variation impacting the pharmacogenomics of childhood acute lymphoblastic leukemia treatment."],"pmcid":["PMC9934807"],"funding_grant_id":["P50 GM115279","R01 CA234490","P30 CA021765","U10 CA180820","U24 CA196172","UG1 CA232760","UG1 CA189859"],"pubmed_authors":["Cheng C","Evans WE","Jeha S","Inaba H","Bergeron BP","Crews KR","Pui CH","Relling MV","Bhattarai KR","Paietta E","Stock W","Diedrich JD","Jabbour E","Yang W","Manring CS","Kornblau SM","Yang JJ","Mobley RJ","Ferguson DC","Pruett-Miller SM","Hansen BS","Litzow MR","Savic D","Barnett KR"],"additional_accession":[]},"is_claimable":false,"name":"Functional investigation of inherited noncoding genetic variation impacting the pharmacogenomics of childhood acute lymphoblastic leukemia treatment.","description":"Although acute lymphoblastic leukemia (ALL) is the most common childhood cancer, there is limited understanding of the contribution of inherited genetic variation on inter-individual differences in chemotherapy response. Defining genetic factors impacting therapy failure can help better predict response and identify drug resistance mechanisms. We therefore mapped inherited noncoding variants associated with chemotherapeutic drug resistance and/or treatment outcome to ALL <i>cis</i>-regulatory elements and investigated their gene regulatory potential and genomic connectivity using massively parallel reporter assays and promoter capture Hi-C, respectively. We identified 53 variants with reproducible allele-specific effects on transcription and high-confidence gene targets. Subsequent functional interrogation of the top variant (rs1247117) determined that it disrupted a PU.1 consensus motif and PU.1 binding affinity. Importantly, deletion of the genomic interval containing rs1247117 sensitized ALL cells to vincristine. Together, these data demonstrate that noncoding regulatory variation associated with diverse pharmacological traits harbor significant effects on allele-specific transcriptional activity and impact sensitivity to chemotherapeutic agents in ALL.","dates":{"release":"2023-01-01T00:00:00Z","publication":"2023 Feb","modification":"2026-04-08T14:41:11.695Z","creation":"2025-02-18T23:44:28.476Z"},"accession":"S-EPMC9934807","cross_references":{"pubmed":["36798219"],"doi":["10.1101/2023.02.10.23285762"]}}