Tang Hongwei, Yan Huihuang, Shivaram Suganti, Lehman Stacey, Sharma Neeraj, Smadbeck James, Zepeda-Mendoza Cinthya, Tian Shulan, Asmann Yan, Vachon Celine, Gaspar Maia Alexandre, Keats Jonathan, Bergsagel P Leif, Fonseca Rafael, Stewart A Keith, Hsu Joel-Sean, Kandasamy Richard K, Pandey Akhilesh, Kaddoura Marcella A, Maura Francesco, Mitra Amit, Rajkumar S Vincent, Kumar Shaji K, Elhaik Eran, Braggio Esteban, Baughn Linda B
Division of Hematopathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
Division of Computational Biology, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA.
Leukemia. 2025 Jan;39(1):42-50. doi: 10.1038/s41375-024-02363-y. Epub 2024 Oct 14.
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.
多发性骨髓瘤（MM）是一种浆细胞（PC）恶性肿瘤，其特征在于细胞遗传学异常，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)最显著的易感等位基因。来自两个独立队列CoMMpass（n = 698）和梅奥诊所（n = 661）的测序数据证实了G等位基因与t(11;14)之间的正相关。在80%携带t(11;14)的rs9344杂合个体中，t(11;14)事件发生在G等位基因上，表明在t(11;14)中对G等位基因有生物学偏好。在t(11;14)中，G等位基因与更高的CCND1表达以及升高的H3K27ac和H3K4me3相关。CRISPR/Cas9介导的A到G转换导致CCND1上的H3K27ac增加以及CCND1表达升高。ENCODE ChIP-seq数据支持在覆盖rs9344的增强子区域内存在一个PAX5结合位点，显示其优先与G等位基因结合。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。
