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, 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 and Daniel Savic ()
Additional contact information
Kashi Raj Bhattarai: St. Jude Children’s Research Hospital
Robert J. Mobley: St. Jude Children’s Research Hospital
Kelly R. Barnett: St. Jude Children’s Research Hospital
Daniel C. Ferguson: St. Jude Children’s Research Hospital
Baranda S. Hansen: St. Jude Children’s Research Hospital
Jonathan D. Diedrich: St. Jude Children’s Research Hospital
Brennan P. Bergeron: St. Jude Children’s Research Hospital
Satoshi Yoshimura: St. Jude Children’s Research Hospital
Wenjian Yang: St. Jude Children’s Research Hospital
Kristine R. Crews: 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
Sima Jeha: St. Jude Children’s Research Hospital
Ching-Hon Pui: St. Jude Children’s Research Hospital
Cheng Cheng: St. Jude Children’s Research Hospital
Shondra M. Pruett-Miller: St. Jude Children’s Research Hospital
Mary V. Relling: St. Jude Children’s Research Hospital
Jun J. Yang: St. Jude Children’s Research Hospital
William E. Evans: St. Jude Children’s Research Hospital
Daniel Savic: St. Jude Children’s Research Hospital

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-48124-4

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