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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE111211 | GEO | 2018/04/25

REPOSITORIES: GEO

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

Project description: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 (Pcombined?=?2.5?×?10-27; ?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.

| S-EPMC5917026 | biostudies-literature

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

Project description:To understand the biological mechanism of ELL2 in multiple myeloma (MM), we show that the MM risk allele lowers ELL2 expression in CD138+ plasma cells (Pcombined=2.5×10-27; bcombined=-0.24 s.d.), 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.

2018-04-25 | GSE111210 | GEO

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

2018-04-25 | GSE111199 | GEO

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

Project description:The multiple myeloma risk allele at 5q15 lowers ELL2 expression and increases ribosomal gene expression [ELL2 rescue]

| PRJNA436170 | ENA

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

Project description:The multiple myeloma risk allele at 5q15 lowers ELL2 expression and increases ribosomal gene expression [ELL2 KO]

| PRJNA436147 | ENA

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

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

| PRJNA436167 | ENA

Variants in ELL2 influencing immunoglobulin levels associate with multiple myeloma.

Project description:Multiple myeloma (MM) is characterized by an uninhibited, clonal growth of plasma cells. While first-degree relatives of patients with MM show an increased risk of MM, the genetic basis of inherited MM susceptibility is incompletely understood. Here we report a genome-wide association study in the Nordic region identifying a novel MM risk locus at ELL2 (rs56219066T; odds ratio (OR)=1.25; P=9.6 × 10(-10)). This gene encodes a stoichiometrically limiting component of the super-elongation complex that drives secretory-specific immunoglobulin mRNA production and transcriptional regulation in plasma cells. We find that the MM risk allele harbours a Thr298Ala missense variant in an ELL2 domain required for transcription elongation. Consistent with a hypomorphic effect, we find that the MM risk allele also associates with reduced levels of immunoglobulin A (IgA) and G (IgG) in healthy subjects (P=8.6 × 10(-9) and P=6.4 × 10(-3), respectively) and, potentially, with an increased risk of bacterial meningitis (OR=1.30; P=0.0024).

| S-EPMC4455110 | biostudies-literature

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

Project description: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.

| S-EPMC5608969 | biostudies-literature

FGF23 is elevated in multiple myeloma and increases heparanase expression by tumor cells.

Project description:Multiply myeloma (MM) grows in and destroys bone, where osteocytes secrete FGF23, a hormone which affects phosphate homeostasis and aging. We report that multiple myeloma (MM) cells express receptors for and respond to FGF23. FGF23 increased mRNA for EGR1 and its target heparanase, a pro-osteolytic factor in MM. FGF23 signals through a complex of klotho and a classical FGF receptor (FGFR); both were expressed by MM cell lines and patient samples. Bone marrow plasma cells from 42 MM patients stained positively for klotho, while plasma cells from 8 patients with monoclonal gammopathy of undetermined significance (MGUS) and 6 controls were negative. Intact, active FGF23 was increased 2.9X in sera of MM patients compared to controls. FGF23 was not expressed by human MM cells, but co-culture with mouse bone increased its mRNA. The FGFR inhibitor NVP-BGJ398 blocked the heparanase response to FGF23. NVP-BGJ398 did not inhibit 8226 growth in vitro but significantly suppressed growth in bone and induction of the osteoclast regulator RANK ligand, while decreasing heparanase mRNA. The bone microenvironment provides resistance to some anti-tumor drugs but increased the activity of NVP-BGJ398 against 8226 cells. The FGF23/klotho/heparanase signaling axis may offer targets for treatment of MM in bone.

| S-EPMC4637311 | biostudies-literature

Identifying a high-risk cellular signature in the multiple myeloma bone marrow microenvironment

Project description:This SuperSeries is composed of the SubSeries listed below.

2019-08-31 | GSE136400 | GEO