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

Area of Science:

• Genetics
• Oncology
• Molecular Biology

Background:

• Multiple myeloma (MM) is a plasma cell malignancy often driven by the t(11;14) chromosomal translocation.
• This translocation leads to CCND1 gene overexpression, a critical event in MM pathogenesis.

Purpose of the Study:

• To investigate the role of the rs9344 single nucleotide polymorphism (SNP) within the CCND1 gene in the context of the t(11;14) translocation in MM.
• To elucidate the molecular mechanisms by which the rs9344 G allele influences CCND1 expression and MM development.

Main Methods:

• Analysis of genetic sequencing data from two independent MM cohorts (CoMMpass and Mayo Clinic).
• Assessing the association between the rs9344 genotype and the presence/characteristics of the t(11;14) translocation.
• Utilizing CRISPR/Cas9 gene editing to convert the rs9344 A to G allele and evaluating its effect on CCND1 expression and epigenetic marks.
• Employing ENCODE ChIP-seq data to identify transcription factor binding sites near rs9344 and assessing the impact of PAX5 overexpression.

Main Results:

• The rs9344 G allele is significantly associated with the t(11;14) translocation in MM patients.
• Individuals with t(11;14) show a biological preference for the t(11;14) event occurring on the rs9344 G allele.
• The G allele is linked to increased CCND1 expression, elevated H3K27ac and H3K4me3 histone modifications.
• CRISPR/Cas9-mediated conversion to the G allele increased H3K27ac and CCND1 expression.
• PAX5 transcription factor preferentially binds to the G allele at the rs9344 enhancer region, leading to increased CCND1 expression.

Conclusions:

• The rs9344 G allele acts as a crucial enhancer element, promoting CCND1 overexpression in multiple myeloma.
• This genetic variation and its interaction with PAX5 binding contribute significantly to the pathogenesis of MM with the t(11;14) translocation.