Functional investigation of inherited noncoding genetic variation impacting the pharmacogenomics of childhood acute
Kashi Raj Bhattarai1,2, Robert J Mobley1,2, Kelly R Barnett1,2
1Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, TN.
Abstract:
Although acute lymphoblastic leukemia (ALL) is the most common childhood cancer, there is limited understanding of the contribution of inherited genetic variation on inter-individual differences in chemotherapy response. Defining genetic factors impacting therapy failure can help better predict response and identify drug resistance mechanisms. We therefore mapped inherited noncoding variants associated with chemotherapeutic drug resistance and/or treatment outcome 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.
Insights
Inherited genetic variations influence childhood acute lymphoblastic leukemia (ALL) treatment outcomes. Identifying these noncoding variants can improve chemotherapy response prediction and reveal drug resistance mechanisms.
Area of Science:
- Genetics
- Oncology
- Pharmacogenomics
Background:
- Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, yet inherited genetic factors influencing chemotherapy response remain poorly understood.
- Identifying genetic determinants of therapy failure is crucial for predicting patient outcomes and elucidating drug resistance pathways.
Approach:
- Mapped inherited noncoding variants to regulatory elements in ALL.
- Utilized massively parallel reporter assays and promoter capture Hi-C to assess gene regulatory potential and genomic connectivity.
- Identified 53 variants affecting transcription and their gene targets, including a key variant (rs1247117) disrupting PU.1 binding.
Key Points:
- Discovered specific noncoding variants linked to chemotherapy resistance and treatment outcomes in ALL.
- Demonstrated that a variant (rs1247117) disrupts transcription factor binding (PU.1).
- Showed that removing this variant's genomic region increases ALL cell sensitivity to vincristine.
Conclusions:
- Noncoding genetic variations significantly impact allele-specific gene expression.
- These variations play a role in modulating sensitivity to chemotherapy agents in acute lymphoblastic leukemia.
- This research provides a foundation for personalized medicine approaches in pediatric ALL treatment.
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