The multiple myeloma risk allele at 5q15 lowers ELL2 expression and increases ribosomal gene expression

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Abstract

Recently, we identified ELL2 as a susceptibility gene for multiple myeloma (MM). To understand its mechanism of action, we performed expression quantitative trait locus analysis in CD138+ plasma cells from 1630 MM patients from four populations. We show that the MM risk allele lowers ELL2 expression in these cells (P combined = 2.5 × 10-27; β combined = -0.24 SD), but not in peripheral blood or other tissues. Consistent with this, several variants representing the MM risk allele map to regulatory genomic regions, and three yield reduced transcriptional activity in plasmocytoma cell lines. One of these (rs3777189-C) co-locates with the best-supported lead variants for ELL2 expression and MM risk, and reduces binding of MAFF/G/K family transcription factors. Moreover, further analysis reveals that the MM risk allele associates with upregulation of gene sets related to ribosome biogenesis, and knockout/knockdown and rescue experiments in plasmocytoma cell lines support a cause-effect relationship. Our results provide mechanistic insight into MM predisposition.

Detaljer

Författare
Enheter & grupper
Externa organisationer
  • University of Arkansas for Medical Sciences
  • Avera Cancer Institute
  • Heidelberg University
  • German Cancer Research Centre
  • Skåne University Hospital
  • Karolinska Institute
  • Norwegian University of Science and Technology
  • Broad Institute
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Medicinsk genetik
Originalspråkengelska
Artikelnummer1649
TidskriftNature Communications
Volym9
Utgivningsnummer1
StatusPublished - 2018 dec 1
PublikationskategoriForskning
Peer review utfördJa

Relaterad forskningsoutput

Ali, M., 2018, Lund: Lund University, Faculty of Medicine. 49 s.

Forskningsoutput: AvhandlingDoktorsavhandling (sammanläggning)

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