TY - JOUR
T1 - Functional variant rs9344 at 11q13.3 regulates CCND1 expression in multiple myeloma with t(11;14)
AU - Tang, Hongwei
AU - Yan, Huihuang
AU - Shivaram, Suganti
AU - Lehman, Stacey
AU - Sharma, Neeraj
AU - Smadbeck, James
AU - Zepeda-Mendoza, Cinthya
AU - Tian, Shulan
AU - Asmann, Yan
AU - Vachon, Celine
AU - Gaspar Maia, Alexandre
AU - Keats, Jonathan
AU - Bergsagel, P. Leif
AU - Fonseca, Rafael
AU - Stewart, A. Keith
AU - Hsu, Joel Sean
AU - Kandasamy, Richard K.
AU - Pandey, Akhilesh
AU - Kaddoura, Marcella A.
AU - Maura, Francesco
AU - Mitra, Amit
AU - Rajkumar, S. Vincent
AU - Kumar, Shaji K.
AU - Elhaik, Eran
AU - Braggio, Esteban
AU - Baughn, Linda B.
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2025/1
Y1 - 2025/1
N2 - 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. (Figure presented.)
AB - 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. (Figure presented.)
UR - https://www.scopus.com/pages/publications/85206794996
UR - https://www.scopus.com/pages/publications/85206794996#tab=citedBy
U2 - 10.1038/s41375-024-02363-y
DO - 10.1038/s41375-024-02363-y
M3 - Article
C2 - 39402215
AN - SCOPUS:85206794996
SN - 0887-6924
VL - 39
SP - 42
EP - 50
JO - Leukemia
JF - Leukemia
IS - 1
M1 - 39
ER -