Leukemia risk factor ARID5B coordinates HDAC-mediated transcriptional repression

Multiple genetic association studies linked variants at ARID5B with predisposition to B-cell-derived acute lymphoblastic leukemia (B-ALL) in children. Still, the molecular function of ARID5B remains largely uncharacterized. Here, we employ a combination of proteomics, genomics, and transcriptomics to describe the molecular mechanisms of ARID5B. We identify that ARID5B interacts with MIER1, C16ORF87, HDAC1, and HDAC2 forming a chromatin repressor complex. By CUT&RUN, we mapped ARID5B binding in active regions of the genome, tethering HDAC1 and HDAC2 to distal regulatory elements and promoters. Genes actively repressed by the ARID5B repressor complex are involved in B-cell proliferation and B-cell-specific signaling. Together, we describe how ARID5B assembles into a repressor complex and regulates B-cell-specific processes. Understanding its molecular mechanism will help elucidating how noncoding germline variants at ARID5B predispose to B-ALL.