GSE225263 Functional investigation of inherited noncoding genetic variation impacting the pharmacogenomics of childhood acute lymphoblastic leukemia treatment [MPRA]

Contributors : Kashi Raj Bhattarai ; Robert J Mobley ; Kelly R Barnett ; Daniel C Ferguson ; Jonathan D Diedrich ; Brennan P Bergeron ; Wenjian Yang ; Kristine R Crews ; Elias Jabbour ; Christopher S Manring ; Elisabeth Paietta ; Steven M Kornblau ; Wendy Stock ; Hiroto Inaba ; Sima Jeha ; Ching-Hon Pui ; Cheng Cheng ; Mary V Relling ; William E Evans ; Jun J Yang ; Daniel SavicSeries Type : OtherOrganism : Homo sapiens ; synthetic constructAlthough acute lymphoblastic leukemia (ALL) is the most prevalent childhood cancer, there is limited understanding of the contribution of inherited genetic variation on inter-individual differences in chemotherapy response, and defining genetic factors impacting therapy failure can help better predict response and identify drug resistance mechanisms. Using inherited noncoding variants associated with chemotherapeutic drug resistance and/or treatment outcome, we mapped these variants to ALL cis-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. T...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Other Homo sapiens synthetic construct Source Type: research