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| Status |
Public on Apr 10, 2024 |
| Title |
Functional investigation of inherited noncoding genetic variation impacting the pharmacogenomics of childhood acute lymphoblastic leukemia treatment [MPRA] |
| Organisms |
Homo sapiens; synthetic construct |
| Experiment type |
Other
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| Summary |
Although 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. 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.
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| Overall design |
MPRA in 10 ALL cell lines
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| Contributor(s) |
Raj Bhattarai K, Mobley RJ, Barnett KR, Ferguson DC, Diedrich JD, Bergeron BP, Yang W, Crews KR, Jabbour E, Manring CS, Paietta E, Kornblau SM, Stock W, Inaba H, Jeha S, Pui C, Cheng C, Relling MV, Evans WE, Yang JJ, Savic D |
| Citation(s) |
38693155 |
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| Submission date |
Feb 14, 2023 |
| Last update date |
May 24, 2024 |
| Contact name |
Daniel Savic |
| E-mail(s) |
daniel.savic@stjude.org
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| Organization name |
St. Jude Children's Research Hospital
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| Department |
Pharmaceutical Sciences
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| Lab |
Savic
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| Street address |
262 Danny Thomas pl.
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| City |
Memphis |
| State/province |
TN |
| ZIP/Postal code |
38105 |
| Country |
USA |
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| Platforms (2) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
| GPL26526 |
Illumina NovaSeq 6000 (synthetic construct) |
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| Samples (64)
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| This SubSeries is part of SuperSeries: |
| GSE224204 |
Functional investigation of inherited noncoding genetic variation impacting the pharmacogenomics of childhood acute lymphoblastic leukemia treatment |
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| Relations |
| BioProject |
PRJNA934850 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE225263_697_MPRA_Counts_AggregateSums.tsv.gz |
42.5 Kb |
(ftp)(http) |
TSV |
| GSE225263_BALL1_MPRA_Counts_AggregateSums.tsv.gz |
36.7 Kb |
(ftp)(http) |
TSV |
| GSE225263_CEM_MPRA_Counts_AggregateSums.tsv.gz |
43.2 Kb |
(ftp)(http) |
TSV |
| GSE225263_DNAInputPDX_MPRA_Counts_AggregateSums.tsv.gz |
45.7 Kb |
(ftp)(http) |
TSV |
| GSE225263_DNAInput_MPRA_Counts_AggregateSums.tsv.gz |
42.9 Kb |
(ftp)(http) |
TSV |
| GSE225263_Jurkat_MPRA_Counts_AggregateSums.tsv.gz |
42.4 Kb |
(ftp)(http) |
TSV |
| GSE225263_MPRA_ALL_CELL_LINES.txt.gz |
773.6 Kb |
(ftp)(http) |
TXT |
| GSE225263_Nalm6_MPRA_Counts_AggregateSums.tsv.gz |
44.1 Kb |
(ftp)(http) |
TSV |
| GSE225263_P12-Ichikawa_MPRA_Counts_AggregateSums.tsv.gz |
43.7 Kb |
(ftp)(http) |
TSV |
| GSE225263_PDX1137_MPRA_Counts_AggregateSums.tsv.gz |
39.6 Kb |
(ftp)(http) |
TSV |
| GSE225263_PDX4420_MPRA_Counts_AggregateSums.tsv.gz |
43.9 Kb |
(ftp)(http) |
TSV |
| GSE225263_REH_MPRA_Counts_AggregateSums.tsv.gz |
36.7 Kb |
(ftp)(http) |
TSV |
| GSE225263_RS411_MPRA_Counts_AggregateSums.tsv.gz |
40.2 Kb |
(ftp)(http) |
TSV |
| GSE225263_SEM_MPRA_Counts_AggregateSums.tsv.gz |
36.3 Kb |
(ftp)(http) |
TSV |
| GSE225263_SUPB15_MPRA_Counts_AggregateSums.tsv.gz |
39.8 Kb |
(ftp)(http) |
TSV |
| GSE225263_barcodes.txt.gz |
1007.2 Kb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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