GSE195831
Molecular mechanisms of ARID5B-mediated genetic susceptibility to acute lymphoblastic leukemia
There is growing evidence for the inherited basis of susceptibility to childhood acute lymphoblastic leukemia (ALL). Genome-wide association studies have identified non-coding ALL risk variants at the ARID5B gene locus, but their exact functional effects and the molecular mechanism linking ARID5B to B-ALL leukemogenesis remain largely unknown. In this study, by targeted sequencing in germline DNA of 5,008 children with ALL, we identified 31 common variants in ARID5B significantly associated with leukemia risk, all of which were non-coding. Six cis-regulatory elements at the ARID5B locus were discovered using CRISPR-based high-throughput enhancer screening. Strikingly, the top ALL risk variant (rs7090445, P=1.82×10-10) is located precisely within the strongest enhancer element, which is also distally tethered to the ARID5B promoter. The rs7090445 variant allele disrupts the MEF2C binding motif sequence, resulting in reduced MEF2C affinity and decreased local chromosome accessibility. MEF2C influences ARID5B expression in ALL, likely via a transcription factor complex with RUNX1. Using the UK Biobank dataset (n=349,861), we showed that rs7090445 was also associated with lymphocyte percentage and count in the general population (P=8.6×10-22 and 2.1×10-18, respectively). Taken together, our results indicate that ALL risk variants in ARID5B function by modulating cis-regulatory elements at this locus. Overall design: Characterize the molecular mechanisms by which non-coding variants contribute to genetic susceptibility to ALL.