TY - JOUR
T1 - Investigation of inherited noncoding genetic variation impacting the pharmacogenomics of childhood acute lymphoblastic leukemia treatment
AU - Bhattarai, Kashi Raj
AU - Mobley, Robert J.
AU - Barnett, Kelly R.
AU - Ferguson, Daniel C.
AU - Hansen, Baranda S.
AU - Diedrich, Jonathan D.
AU - Bergeron, Brennan P.
AU - Yoshimura, Satoshi
AU - Yang, Wenjian
AU - Crews, Kristine R.
AU - Manring, Christopher S.
AU - Jabbour, Elias
AU - Paietta, Elisabeth
AU - Litzow, Mark R.
AU - Kornblau, Steven M.
AU - Stock, Wendy
AU - Inaba, Hiroto
AU - Jeha, Sima
AU - Pui, Ching Hon
AU - Cheng, Cheng
AU - Pruett-Miller, Shondra M.
AU - Relling, Mary V.
AU - Yang, Jun J.
AU - Evans, William E.
AU - Savic, Daniel
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/12
Y1 - 2024/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-024-48124-4
DO - 10.1038/s41467-024-48124-4
M3 - Article
C2 - 38693155
AN - SCOPUS:85191707955
SN - 2041-1723
VL - 15
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 3681
ER -