在11q13.3的功能变异RS9344调节多发性骨髓瘤中的CCND1表达（11; 14）
Functional variant rs9344 at 11q13.3 regulates CCND1 expression in multiple myeloma with t(11;14)
影响因子:13.40000
分区:医学1区 Top / 血液学1区 肿瘤学2区
发表日期:2025 Jan
作者:
Hongwei Tang, Huihuang Yan, Suganti Shivaram, Stacey Lehman, Neeraj Sharma, James Smadbeck, Cinthya Zepeda-Mendoza, Shulan Tian, Yan Asmann, Celine Vachon, Alexandre Gaspar Maia, Jonathan Keats, P Leif Bergsagel, Rafael Fonseca, A Keith Stewart, Joel-Sean Hsu, Richard K Kandasamy, Akhilesh Pandey, Marcella A Kaddoura, Francesco Maura, Amit Mitra, S Vincent Rajkumar, Shaji K Kumar, Eran Elhaik, Esteban Braggio, Linda B Baughn
摘要
多发性骨髓瘤（MM）是浆细胞（PC）恶性肿瘤，其特征是细胞遗传学异常，例如T（11; 14）（Q13; Q32），导致CCND1过表达。 CCND1内的RS9344 G等位基因是T（11; 14）的最重要的敏感性等位基因。测序来自2个独立队列的数据，CommPass（n = 698）和Mayo Clinic（n = 661），确认G等位基因与T（11; 14）之间的正相关。在具有t（11; 14）的rs9344的杂合子中，有80％的个体发生在G等位基因上的t（11; 14）事件发生，表明t（11; 14）中G等位基因的生物学偏爱。在t（11; 14）中，G等位基因与较高的CCND1表达以及H3K27AC和H3K4ME3升高有关。 CRISPR/CAS9介导的A至G转换导致CCND1上H3K27AC增加，CCND1表达升高。编码CHIP-SEQ数据支持覆盖RS9344的增强剂区域内的PAX5结合位点，显示出与G等位基因的优先结合。 PAX5的过表达导致CCND1表达增加。这些结果支持RS9344 G增强子在增加MM中CCND1表达方面的重要性。
Abstract
Multiple myeloma (MM) is a plasma cell (PC) malignancy characterized by cytogenetic abnormalities, such as t(11;14)(q13;q32), resulting in CCND1 overexpression. The rs9344 G allele within CCND1 is 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 CCND1 expression and elevated H3K27ac and H3K4me3. CRISPR/Cas9 mediated A to G conversion resulted in increased H3K27ac over CCND1 and elevated CCND1 expression. ENCODE ChIP-seq data supported a PAX5 binding site within the enhancer region covering rs9344, showing preferential binding to the G allele. Overexpression of PAX5 resulted in increased CCND1 expression. These results support the importance of rs9344 G enhancer in increasing CCND1 expression in MM.