Functional variant rs9344 at 11q13.3 regulates CCND1expression in multiple myeloma with t(11;14)

Multiple myeloma (MM) is a plasma cell (PC) malignancy characterized by cytogenetic abnormalities, such as t(11;14)(q13;q32), resulting in CCND1overexpression. The rs9344 G allele within CCND1is the most significant susceptibility allele for t(11;14). Sequencing data from 2 independent cohorts, CoMMpass (n= 698) and Mayo Clinic (n= 661), confirm the positive association between the G allele and t(11;14). Among 80% of individuals heterozygous for rs9344 with t(11;14), the t(11;14) event occurs on the G allele, demonstrating a biological preference for the G allele in t(11;14). Within t(11;14), the G allele is associated with higher CCND1expression and elevated H3K27ac and H3K4me3. CRISPR/Cas9 mediated A to G conversion resulted in increased H3K27ac over CCND1and elevated CCND1expression. ENCODE ChIP-seq data supported a PAX5 binding site within the enhancer region covering rs9344, showing preferential binding to the G allele. Overexpression of PAX5resulted in increased CCND1expression. These results support the importance of rs9344 G enhancer in increasing CCND1expression in MM.