Study / S62L6CVHB2024-05-01

Investigation of inherited noncoding genetic variation impacting the pharmacogenomics of childhood acute lymphoblastic leukemia treatment

Kashi Raj Bhattarai, Robert J. Mobley, Kelly R. Barnett, Daniel C. Ferguson, Baranda S. Hansen et al.

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About this study

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.

Full author list & citation

Kashi Raj Bhattarai, Robert J. Mobley, Kelly R. Barnett, Daniel C. Ferguson, Baranda S. Hansen, Jonathan D. Diedrich, Brennan P. Bergeron, Satoshi Yoshimura, Wenjian Yang, Kristine R. Crews, Christopher S. Manring, Elias Jabbour, Elisabeth Paietta, Mark R. Litzow, Steven M. Kornblau, Wendy Stock, Hiroto Inaba, Sima Jeha, Ching-Hon Pui, Cheng Cheng, Shondra M. Pruett-Miller, Mary V. Relling, Jun J. Yang, William E. Evans, Daniel Savic. Investigation of inherited noncoding genetic variation impacting the pharmacogenomics of childhood acute lymphoblastic leukemia treatment. 2024-05-01. https://doi.org/10.1038/s41467-024-48124-4

Experiments 2

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Allele-specific plasmid MPRA across 10 acute lymphoblastic leukemia cell lines

A plasmid library containing 175-bp sequences centered on 1,696 reference/alternative regulatory SNVs was tested in seven B-ALL cell lines (697, BALL1, Nalm6, REH, RS411, SEM, SUPB15) and three T-ALL cell lines (CEM, Jurkat, P12-Ichikawa). Each allele was represented by 28 unique 3′-UTR barcodes and each cell line had four transfections; table.csv retains one row per variant–phenotype–cell-line result with the authors’ differential statistics and count-derived allele activities.

Episomal Plasmid MPRAHumanhg19

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E8LZFVT59

Allele-specific plasmid MPRA in B-ALL patient-derived xenograft samples

The same 1,696-variant plasmid MPRA library was tested in two pediatric B-ALL patient-derived xenograft samples, PDXMPRA1137 and PDXMPRA4420, with four transfections per sample. table.csv contains all variant-level count-supported results for both final GEO runs, plus the authors’ reported significant-hit annotations where available.

Episomal Plasmid MPRAHumanhg19

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Raw source data 27 files

Original supplemental and deposited inputs retained for this study. Download files individually or together as a ZIP; nested folders are preserved. Source reuse terms apply, and sequencing reads may be omitted.