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

Author

Listed:
  • Kashi Raj Bhattarai

    (St. Jude Children’s Research Hospital
    St. Jude Children’s Research Hospital)

  • Robert J. Mobley

    (St. Jude Children’s Research Hospital
    St. Jude Children’s Research Hospital)

  • Kelly R. Barnett

    (St. Jude Children’s Research Hospital
    St. Jude Children’s Research Hospital)

  • Daniel C. Ferguson

    (St. Jude Children’s Research Hospital
    St. Jude Children’s Research Hospital)

  • Baranda S. Hansen

    (St. Jude Children’s Research Hospital
    St. Jude Children’s Research Hospital)

  • Jonathan D. Diedrich

    (St. Jude Children’s Research Hospital
    St. Jude Children’s Research Hospital)

  • Brennan P. Bergeron

    (St. Jude Children’s Research Hospital
    St. Jude Children’s Research Hospital
    St. Jude Children’s Research Hospital)

  • Satoshi Yoshimura

    (St. Jude Children’s Research Hospital
    St. Jude Children’s Research Hospital
    Tohoku University School of Medicine)

  • Wenjian Yang

    (St. Jude Children’s Research Hospital
    St. Jude Children’s Research Hospital)

  • Kristine R. Crews

    (St. Jude Children’s Research Hospital
    St. Jude Children’s Research Hospital)

  • Christopher S. Manring

    (Alliance Hematologic Malignancy Biorepository; Clara D. Bloomfield Center for Leukemia Outcomes Research)

  • Elias Jabbour

    (The University of Texas MD Anderson Cancer Center)

  • Elisabeth Paietta

    (Albert Einstein College of Medicine)

  • Mark R. Litzow

    (Department of Medicine, Mayo Clinic)

  • Steven M. Kornblau

    (The University of Texas MD Anderson Cancer Center)

  • Wendy Stock

    (University of Chicago Medicine)

  • Hiroto Inaba

    (St. Jude Children’s Research Hospital
    St. Jude Children’s Research Hospital)

  • Sima Jeha

    (St. Jude Children’s Research Hospital
    St. Jude Children’s Research Hospital)

  • Ching-Hon Pui

    (St. Jude Children’s Research Hospital
    St. Jude Children’s Research Hospital)

  • Cheng Cheng

    (St. Jude Children’s Research Hospital)

  • Shondra M. Pruett-Miller

    (St. Jude Children’s Research Hospital
    St. Jude Children’s Research Hospital)

  • Mary V. Relling

    (St. Jude Children’s Research Hospital
    St. Jude Children’s Research Hospital)

  • Jun J. Yang

    (St. Jude Children’s Research Hospital
    St. Jude Children’s Research Hospital
    St. Jude Children’s Research Hospital
    University of Tennessee Health Science Center)

  • William E. Evans

    (St. Jude Children’s Research Hospital
    St. Jude Children’s Research Hospital)

  • Daniel Savic

    (St. Jude Children’s Research Hospital
    St. Jude Children’s Research Hospital
    St. Jude Children’s Research Hospital
    University of Tennessee Health Science Center)

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.

Suggested 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 &, 2024. "Investigation of inherited noncoding genetic variation impacting the pharmacogenomics of childhood acute lymphoblastic leukemia treatment," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48124-4
    DOI: 10.1038/s41467-024-48124-4
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    References listed on IDEAS

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