Abstract 3199: Investigating gene regulatory mechanisms associated with B-cell acute lymphoblastic leukemia incidence in Hispanic/Latino populations

Abstract B-cell acute lymphoblastic leukemia (B-ALL) is the most common childhood cancer. In the United States, Hispanic/Latino children exhibit a higher incidence and lower overall survival than non-Hispanic White patients, independent of social determinants. Genome-wide association studies have identified several single-nucleotide polymorphisms (SNPs) associated with B-ALL risk, including a recurrent variant, rs7090445, located in intron 3 of the ARID5B gene locus. The rs7090445 risk allele (C) is ∼36% more common in Latino/Admixed-American individuals than in non-Latino Whites and rises with Indigenous-American ancestry, highlighting its potential role in B-ALL incidence disparities. The rs7090445 SNP resides within a lymphoid-specific enhancer that physically interacts with the ARID5B promoter. However, the role of this non-coding variant in B-cell transformation remains unclear. In humans, ARID5B mRNA expression increases at the pro-B cell stage, subsequently peaking at the pre-B stage. In mice, Arid5b deletion causes a differentiation delay at the pre-B stage, highlighting the importance of Arid5b dosage in B cell progenitor maturation. We hypothesize the B-ALL-associated ARID5B SNP rs7090445 perturbs enhancer function and disrupts normal B-cell development by reshaping the epigenetic landscape governing ARID5B transcription. To investigate this, we analyzed primary B-ALL patient and healthy bone marrow donor ATAC-Seq and RNA-seq datasets to define how the SNP influences chromatin accessibility, transcription factor occupancy, and gene expression across specific lymphoid subpopulations. These analyses revealed the rs7090445 risk allele elicited pro-B cell-specific reductions in ARID5B intronic enhancer accessibility and ARID5B transcription, with ongoing analysis dissecting genome-wide chromatin accessibility footprints. To functionally dissect these observations, we generated isogenic B-ALL cell clones harboring the rs7090445 risk and non-risk allele. Analyses of these engineered lines recapitulate allele-specific differences observed in patient samples, supporting a direct role for rs7090445 in modulating enhancer function and ARID5B gene activation. Ongoing studies aim to map SNP-altered transcription factor footprints and validate candidate regulators in B-ALL cell lines and patient-derived xenograft models. These findings provide a rationale for investigating how rs7090445 may perturb gene-regulatory networks influencing B-cell development and B-ALL. Citation Format: Clarissa Garcia, Julian Grandvallet Contreras, Tzu Phang, Matthew T. Witkowski. Investigating gene regulatory mechanisms associated with B-cell acute lymphoblastic leukemia incidence in Hispanic/Latino populations abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3199.