染色体11q13.3处功能性变异rs9344调控多发性骨髓瘤中CCND1的表达，伴随t(11;14)染色体易位

Functional variant rs9344 at 11q13.3 regulates CCND1 expression in multiple myeloma with t(11;14)

LEUKEMIA

影响因子:13.4

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

DOI: 10.1038/s41375-024-02363-y

摘要

多发性骨髓瘤（MM）是一种浆细胞（PC）恶性肿瘤，伴有染色体遗传异常，如t(11;14)(q13;q32)，导致CCND1过表达。位于CCND1基因内的rs9344 G等位基因是与t(11;14)最显著相关的易感等位基因。来自两个独立队列（CoMMpass，n=698；Mayo Clinic，n=661）的测序数据验证了G等位基因与t(11;14)之间的正相关。在80%的携带t(11;14)的异质合子个体中，t(11;14)事件发生在G等位基因上，显示出对G等位基因的生物学偏好。在t(11;14)中，G等位基因与较高的CCND1表达以及H3K27ac和H3K4me3的增强相关。利用CRISPR/Cas9技术将A突变为G，导致CCND1区域H3K27ac增加和CCND1表达上调。ENCODE的ChIP-seq数据显示，rs9344所在的增强子区域存在PAX5的结合位点，并倾向于G等位基因结合。PAX5过表达也能增加CCND1的表达。这些结果支持rs9344 G等位基因的增强子在MM中调控CCND1表达的重要性。

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.