Functional Variant Rs9344 at 11q13.3 Regulates CCND1 Expression in Multiple Myeloma with T(11;14)

Overview

Journal Leukemia

Specialties Hematology
Oncology

Date 2024 Oct 14

PMID 39402215

Authors

Hongwei Tang

Huihuang Yan

Suganti Shivaram

Stacey Lehman

Neeraj Sharma

James Smadbeck

Cinthya Zepeda-Mendoza

Shulan Tian

Yan Asmann

Celine Vachon

Alexandre Gaspar Maia

Jonathan Keats

P Leif Bergsagel

Rafael Fonseca

A Keith Stewart

Joel-Sean Hsu

Richard K Kandasamy

Akhilesh Pandey

Marcella A Kaddoura

Francesco Maura

Amit Mitra

S Vincent Rajkumar

Shaji K Kumar

Eran Elhaik

Esteban Braggio

Linda B Baughn

Affiliations

Soon will be listed here.

Abstract

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.

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