The University of Southampton
University of Southampton Institutional Repository
Warning ePrints Soton is experiencing an issue with some file downloads not being available. We are working hard to fix this. Please bear with us.

Genetic Predisposition to Multiple Myeloma at 5q15 Is Mediated by an ELL2 Enhancer Polymorphism

Genetic Predisposition to Multiple Myeloma at 5q15 Is Mediated by an ELL2 Enhancer Polymorphism
Genetic Predisposition to Multiple Myeloma at 5q15 Is Mediated by an ELL2 Enhancer Polymorphism

Multiple myeloma (MM) is a malignancy of plasma cells. Genome-wide association studies have shown that variation at 5q15 influences MM risk. Here, we have sought to decipher the causal variant at 5q15 and the mechanism by which it influences tumorigenesis. We show that rs6877329 G > C resides in a predicted enhancer element that physically interacts with the transcription start site of ELL2. The rs6877329-C risk allele is associated with reduced enhancer activity and lowered ELL2 expression. Since ELL2 is critical to the B cell differentiation process, reduced ELL2 expression is consistent with inherited genetic variation contributing to arrest of plasma cell development, facilitating MM clonal expansion. These data provide evidence for a biological mechanism underlying a hereditary risk of MM at 5q15.

Alleles, Chromosomes, Human, Pair 5, Diploidy, Enhancer Elements, Genetic, Epigenesis, Genetic, Epigenomics, Genetic Loci, Genetic Predisposition to Disease, Humans, Multiple Myeloma, Nuclear Proteins, Physical Chromosome Mapping, Polymorphism, Single Nucleotide, Prognosis, Protein Binding, Risk Factors, Transcription Elongation, Genetic, Transcriptional Elongation Factors, Unfolded Protein Response, Journal Article
2211-1247
2556-2564
Li, Ni
b047d2c1-98de-4d16-b44e-057b032ab898
Johnson, David C.
37fc5be7-f918-4646-9224-136f3a0ef557
Weinhold, Niels
ba9220dd-e751-4b3a-a519-e3787752a083
Kimber, Scott
912df707-c67a-42eb-8f6d-5395e7397d38
Dobbins, Sara E
587028e6-a073-4f99-a62c-6012ce4ac1e5
Mitchell, Jonathan S
4e16747a-68e0-4660-b540-8b0af8f7855b
Kinnersley, Ben
60b20abb-8a16-48c8-b4bc-e7d25ddb2af2
Sud, Amit
fcd5d252-8f84-40c5-a2b8-dad5fc301c17
Law, Philip J
3c609adc-2aea-4fbb-8440-77e536a9292a
Orlando, Giulia
1e716170-59cd-4553-80d3-78ad472bd192
Scales, Matthew
987e1cec-816e-4111-93e0-d9e76bb6b4de
Wardell, Christopher P
0d498cee-324b-457c-adff-7193c16cf2d5
Försti, Asta
50654f61-4eda-4eba-944b-041026370190
Hoang, Phuc H
c8f2be93-8eb7-456d-b70e-50c1dd796e76
Went, Molly
10a6d44c-0ff6-4546-a364-9ee15bca0ddd
Holroyd, Amy
7334d47c-e767-4a83-ad43-c94f9900b214
Hariri, Fadi
1cdd0e97-176e-467c-b766-7d26a993e9db
Pastinen, Tomi
09f7db30-28b0-4ec2-9128-05985d113078
Meissner, Tobias
05292b80-8165-49ae-9fcb-bc9bcb926ce7
Goldschmidt, Hartmut
f0cecca6-05ba-4462-8fa5-5bb85d0db5ad
Hemminki, Kari
4ce7a3f5-a609-4efd-b87d-1e8d0f9fc191
Morgan, Gareth J
d285dcf8-ac2c-4fe0-acf9-4787eb025939
Kaiser, Martin
06cc69df-57a7-405d-abc8-06a6ae1cdc78
Houlston, Richard S
0292e06f-2fd2-4b71-a629-00b288016474
Li, Ni
b047d2c1-98de-4d16-b44e-057b032ab898
Johnson, David C.
37fc5be7-f918-4646-9224-136f3a0ef557
Weinhold, Niels
ba9220dd-e751-4b3a-a519-e3787752a083
Kimber, Scott
912df707-c67a-42eb-8f6d-5395e7397d38
Dobbins, Sara E
587028e6-a073-4f99-a62c-6012ce4ac1e5
Mitchell, Jonathan S
4e16747a-68e0-4660-b540-8b0af8f7855b
Kinnersley, Ben
60b20abb-8a16-48c8-b4bc-e7d25ddb2af2
Sud, Amit
fcd5d252-8f84-40c5-a2b8-dad5fc301c17
Law, Philip J
3c609adc-2aea-4fbb-8440-77e536a9292a
Orlando, Giulia
1e716170-59cd-4553-80d3-78ad472bd192
Scales, Matthew
987e1cec-816e-4111-93e0-d9e76bb6b4de
Wardell, Christopher P
0d498cee-324b-457c-adff-7193c16cf2d5
Försti, Asta
50654f61-4eda-4eba-944b-041026370190
Hoang, Phuc H
c8f2be93-8eb7-456d-b70e-50c1dd796e76
Went, Molly
10a6d44c-0ff6-4546-a364-9ee15bca0ddd
Holroyd, Amy
7334d47c-e767-4a83-ad43-c94f9900b214
Hariri, Fadi
1cdd0e97-176e-467c-b766-7d26a993e9db
Pastinen, Tomi
09f7db30-28b0-4ec2-9128-05985d113078
Meissner, Tobias
05292b80-8165-49ae-9fcb-bc9bcb926ce7
Goldschmidt, Hartmut
f0cecca6-05ba-4462-8fa5-5bb85d0db5ad
Hemminki, Kari
4ce7a3f5-a609-4efd-b87d-1e8d0f9fc191
Morgan, Gareth J
d285dcf8-ac2c-4fe0-acf9-4787eb025939
Kaiser, Martin
06cc69df-57a7-405d-abc8-06a6ae1cdc78
Houlston, Richard S
0292e06f-2fd2-4b71-a629-00b288016474

Li, Ni, Johnson, David C., Weinhold, Niels, Kimber, Scott, Dobbins, Sara E, Mitchell, Jonathan S, Kinnersley, Ben, Sud, Amit, Law, Philip J, Orlando, Giulia, Scales, Matthew, Wardell, Christopher P, Försti, Asta, Hoang, Phuc H, Went, Molly, Holroyd, Amy, Hariri, Fadi, Pastinen, Tomi, Meissner, Tobias, Goldschmidt, Hartmut, Hemminki, Kari, Morgan, Gareth J, Kaiser, Martin and Houlston, Richard S (2017) Genetic Predisposition to Multiple Myeloma at 5q15 Is Mediated by an ELL2 Enhancer Polymorphism. Cell Reports, 20 (11), 2556-2564. (doi:10.1016/j.celrep.2017.08.062).

Record type: Article

Abstract

Multiple myeloma (MM) is a malignancy of plasma cells. Genome-wide association studies have shown that variation at 5q15 influences MM risk. Here, we have sought to decipher the causal variant at 5q15 and the mechanism by which it influences tumorigenesis. We show that rs6877329 G > C resides in a predicted enhancer element that physically interacts with the transcription start site of ELL2. The rs6877329-C risk allele is associated with reduced enhancer activity and lowered ELL2 expression. Since ELL2 is critical to the B cell differentiation process, reduced ELL2 expression is consistent with inherited genetic variation contributing to arrest of plasma cell development, facilitating MM clonal expansion. These data provide evidence for a biological mechanism underlying a hereditary risk of MM at 5q15.

Text
1-s2.0-S2211124717311877-main - Version of Record
Available under License Creative Commons Attribution.
Download (3MB)

More information

Published date: 12 September 2017
Keywords: Alleles, Chromosomes, Human, Pair 5, Diploidy, Enhancer Elements, Genetic, Epigenesis, Genetic, Epigenomics, Genetic Loci, Genetic Predisposition to Disease, Humans, Multiple Myeloma, Nuclear Proteins, Physical Chromosome Mapping, Polymorphism, Single Nucleotide, Prognosis, Protein Binding, Risk Factors, Transcription Elongation, Genetic, Transcriptional Elongation Factors, Unfolded Protein Response, Journal Article

Identifiers

Local EPrints ID: 429890
URI: http://eprints.soton.ac.uk/id/eprint/429890
ISSN: 2211-1247
PURE UUID: d9de17d1-d977-471a-b4e7-b3403f30e384

Catalogue record

Date deposited: 08 Apr 2019 16:30
Last modified: 21 Nov 2021 16:03

Export record

Altmetrics

Contributors

Author: Ni Li
Author: David C. Johnson
Author: Niels Weinhold
Author: Scott Kimber
Author: Sara E Dobbins
Author: Jonathan S Mitchell
Author: Ben Kinnersley
Author: Amit Sud
Author: Philip J Law
Author: Giulia Orlando
Author: Matthew Scales
Author: Christopher P Wardell
Author: Asta Försti
Author: Phuc H Hoang
Author: Molly Went
Author: Amy Holroyd
Author: Fadi Hariri
Author: Tomi Pastinen
Author: Tobias Meissner
Author: Hartmut Goldschmidt
Author: Kari Hemminki
Author: Gareth J Morgan
Author: Martin Kaiser
Author: Richard S Houlston

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×