Functional variant rs9344 at 11q13.3 regulates CCND1 expression in multiple myeloma with t(11;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.
Authors
- Rafaël Fonseca (ORCID: https://orcid.org/0000-0002-5938-3769)
- P. Leif Bergsagel (ORCID: https://orcid.org/0000-0003-1523-7388)
- Amit Mitra (ORCID: https://orcid.org/0000-0003-4046-7070)
- Yan W. Asmann (ORCID: https://orcid.org/0000-0002-8896-2647)
- Hongwei Tang (ORCID: https://orcid.org/0000-0002-2053-788X)
- Akhilesh Pandey (ORCID: https://orcid.org/0000-0001-9943-6127)
- Shaji Kunnathu Kumar (ORCID: https://orcid.org/0000-0001-5392-9284)
- Linda Banovic Baughn (ORCID: https://orcid.org/0000-0001-5229-4897)
- Suganti Shivaram
- Alexandre Gaspar‐Maia (ORCID: https://orcid.org/0000-0001-8528-5575)
- Eran Elhaik (ORCID: https://orcid.org/0000-0003-4795-1084)
- Neeraj Sharma (ORCID: https://orcid.org/0000-0002-8229-3083)
- Cinthya J. Zepeda‐Mendoza (ORCID: https://orcid.org/0000-0002-0434-4965)
- Celine M. Vachon
- Stacey L. Lehman (ORCID: https://orcid.org/0000-0001-7029-4719)
- Marcella Kaddoura (ORCID: https://orcid.org/0000-0002-4529-7405)
- S. Vincent Rajkumar (ORCID: https://orcid.org/0000-0002-5862-1833)
- James B. Smadbeck (ORCID: https://orcid.org/0000-0002-8902-0950)
- Esteban Braggio (ORCID: https://orcid.org/0000-0003-3860-4830)
- Richard K. Kandasamy (ORCID: https://orcid.org/0000-0002-0894-1222)
- Huihuang Yan (ORCID: https://orcid.org/0000-0003-0756-2922)
- Jonathan J. Keats (ORCID: https://orcid.org/0000-0003-4375-7399)
- Francesco Maura (ORCID: https://orcid.org/0000-0002-5017-1620)
- A. Keith Stewart
- Joel-Sean Hsu
- Shulan Tian (ORCID: https://orcid.org/0000-0002-3348-7439)
Institutions
- Translational Genomics Research Institute (US)
- Mayo Clinic (US)
- University of Miami (US)
- Manipal Academy of Higher Education (IN)
- Lund University (SE)
- Princess Margaret Cancer Centre (CA)
- Mayo Clinic in Arizona (US)
- Mayo Clinic in Florida (US)
- Sylvester Comprehensive Cancer Center (US)
- Auburn University (US)
Publication Details
- Journal
- Leukemia
- Published
- 2024-10-14
- DOI
- https://doi.org/10.1038/s41375-024-02363-y
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Mayo Clinic
- National Institutes of Health
- National Cancer Institute
- Division of Cancer Epidemiology and Genetics, National Cancer Institute