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

被引：0

作者：

Tang, Hongwei ^{[1
]}

Yan, Huihuang ^{[2
]}

Shivaram, Suganti ^{[1
]}

Lehman, Stacey ^{[1
]}

Sharma, Neeraj ^{[1
]}

Smadbeck, James ^{[3
]}

Zepeda-Mendoza, Cinthya ^{[1
]}

Tian, Shulan ^{[2
]}

Asmann, Yan ^{[4
]}

Vachon, Celine ^{[5
]}

Maia, Alexandre Gaspar ^{[6
]}

Keats, Jonathan ^{[7
]}

Bergsagel, P. Leif ^{[8
]}

Fonseca, Rafael ^{[8
]}

Stewart, A. Keith ^{[9
]}

Hsu, Joel-Sean ^{[10
]}

Kandasamy, Richard K. ^{[2
,6
,11
]}

Pandey, Akhilesh ^{[6
,11
,12
]}

Kaddoura, Marcella A. ^{[13
]}

Maura, Francesco ^{[13
]}

Mitra, Amit ^{[14
]}

Rajkumar, S. Vincent ^{[15
]}

Kumar, Shaji K. ^{[15
]}

Elhaik, Eran ^{[16
]}

Braggio, Esteban ^{[8
]}

Baughn, Linda B. ^{[1
]}

机构：

[1] Mayo Clin, Dept Lab Med & Pathol, Div Hematopathol, Rochester, MN 55905 USA

[2] Mayo Clin, Dept Quantitat Hlth Sci, Div Computat Biol, Rochester, MN USA

[3] Mayo Clin, Ctr Individualized Med Biomarker Discovery, Rochester, MN USA

[4] Mayo Clin, Dept Hlth Sci Res, Div Computat Biol, Jacksonville, FL USA

[5] Mayo Clin, Dept Quantitat Hlth Sci, Div Epidemiol, Rochester, MN USA

[6] Mayo Clin, Dept Lab Med & Pathol, Div Expt Pathol & Lab Med, Rochester, MN USA

[7] Translat Genom Res Inst TGen, Integrated Canc Genom, Phoenix, AZ USA

[8] Mayo Clin, Dept Internal Med, Div Hematol, Scottsdale, AZ USA

[9] Princess Margaret Canc Ctr, Toronto, ON, Canada

[10] Mayo Clin, Dept Biochem & Mol Biol, Rochester, MN USA

[11] Mayo Clin, Ctr Individualized Med, Rochester, MN USA

[12] Manipal Acad Higher Educ, Manipal, Karnataka, India

[13] Univ Miami, Sylvester Comprehens Canc Ctr, Dept Med, Div Myeloma, Miami, FL USA

[14] Auburn Univ, Drug Discovery & Dev, Auburn, AL USA

[15] Mayo Clin, Dept Internal Med, Div Hematol, Rochester, MN USA

[16] Lund Univ, Dept Biol, Lund, Sweden

来源：

LEUKEMIA | 2025年 / 39卷 / 01期

基金：

美国国家卫生研究院;

关键词：

CELL IDENTITY; PAX5; POLYMORPHISM; ENHANCERS; CHROMATIN; GENOME;

D O I：

10.1038/s41375-024-02363-y

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：42 / 50

页数：9

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