Alterations in bone marrow metabolism are an early and consistent feature during the development of MGUS and multiple myeloma

Ludwig, Christian; Williams, D. R.; Bartlett, David B.; Essex, Sarah; McNee, Gavin; Allwood, J. William; Jewell, Emilia; Barkhuisen, A; Parry, Helen; Anandram, Seetharam; Nicolson, Phillip L.R.; Gardener, Carole; Seymour, Frances; Basu, Supratik; Dunn, Warwick B.; Moss, Paul; Pratt, Guy; Tennant, Daniel A.

doi:10.1038/bcj.2015.85

Cited by 22 publications

(24 citation statements)

References 17 publications

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“…We demonstrate here that BMMSCs from patients with both MGUS and MM have a transformed transcriptome compared with those from healthy individuals, in agreement with previous results. 7 Our data, alongside those of others and our previous metabolomic study 35 highlight the significant similarities between the microenvironment of the BM in MGUS and MM, suggesting that transformation of the BM microenvironment is an early event in disease aetiology, raising the potential of interfering with this process in order to delay or prevent progression of patients with MGUS to MM. In addition, these data further highlight a need to identify those biological determinants in the BM that actually contribute to the progression of this disease: whether these are active drivers, or release of inhibitors of malignant progression.…”

Section: Discussionsupporting

confidence: 75%

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Citrullination of histone H3 drives IL-6 production by bone marrow mesenchymal stem cells in MGUS and multiple myeloma

et al. 2016

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Multiple myeloma (MM), an incurable plasma cell malignancy, requires localisation within the bone marrow. This microenvironment facilitates crucial interactions between the cancer cells and stromal cell types that permit the tumour to survive and proliferate. There is increasing evidence that the bone marrow mesenchymal stem cell (BMMSC) is stably altered in patients with MM—a phenotype also postulated to exist in patients with monoclonal gammopathy of undetermined significance (MGUS) a benign condition that precedes MM. In this study, we describe a mechanism by which increased expression of peptidyl arginine deiminase 2 (PADI2) by BMMSCs in patients with MGUS and MM directly alters malignant plasma cell phenotype. We identify PADI2 as one of the most highly upregulated transcripts in BMMSCs from both MGUS and MM patients, and that through its enzymatic deimination of histone H3 arginine 26, PADI2 activity directly induces the upregulation of interleukin-6 expression. This leads to the acquisition of resistance to the chemotherapeutic agent, bortezomib, by malignant plasma cells. We therefore describe a novel mechanism by which BMMSC dysfunction in patients with MGUS and MM directly leads to pro-malignancy signalling through the citrullination of histone H3R26.

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Section: Discussionsupporting

confidence: 75%

“…Interestingly, we recently published evidence that urea concentrations are significantly increased in the bone marrow plasma of patients with both MGUS and MM, consistent with significantly increased cellular production of ammonium, perhaps through PADI2 activity, in the bone marrow niche. 35 …”

Section: Resultsmentioning

confidence: 99%

Citrullination of histone H3 drives IL-6 production by bone marrow mesenchymal stem cells in MGUS and multiple myeloma

et al. 2016

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“…Almost all HMCLs have primary MYC translocations involving an immunoglobulin gene locus, making their levels of c-MYC expression high (22). Other metabolomic-based approaches have been undertaken in the past using archived biofluids such as peripheral blood and urine samples from patients with MM (27)(28)(29). Though these studies were different from this study, as they utilized an untargeted metabolite profiling methodology via NMR spectroscopy, they were able to identify metabolite profiles that correlated with the presence of either active disease, remission, or precursor states such as MGUS.…”

Section: Discussionmentioning

confidence: 99%

Glutamine-derived 2-hydroxyglutarate is associated with disease progression in plasma cell malignancies

Gonsalves¹,

Ramakrishnan²,

Hitosugi³

et al. 2018

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“…An increased kynurenine/tryptophan ratio and lower ADMA levels again could be detected in MGUS patients. Metabolic alterations of several different biochemical classes in the bone marrow environment from MGUS patients were recently reported [ 11 ]. These changes, especially for the lipid metabolism, could also be observed in our study with peripheral blood.…”

Section: Discussionmentioning

confidence: 99%

“…Inhibition of LDHA and HIF1A can restore sensitivity to therapeutic drugs such as bortezomib [ 10 ]. Ludwig et al highlights alterations in bone marrow metabolism as an early feature of the development of MGUS and MM [ 11 ]. Despite the interest in metabolomics of MM, the role and potential application in diagnostics, classification and prediction of therapy response remains unclear.…”

Section: Introductionmentioning

confidence: 99%

The metabolomic plasma profile of myeloma patients is considerably different from healthy subjects and reveals potential new therapeutic targets

et al. 2018

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IntroductionMultiple myeloma (MM), a malignant plasma cell disorder, is still an incurable disease. Thus, the identification of novel therapeutic targets is of utmost importance. Here, we evaluated the peripheral blood-based metabolic profile of patients with MM.Material & methodsPeripheral blood plasma levels of 188 endogenous metabolites, including amino acids, biogenic amines, acylcarnitines, glycerophospholipids, sphingomyelins, and hexoses were determined in patients with plasma cell dyscrasias: monoclonal gammopathy of undetermined significance, a precursor stage of MM (MGUS, n = 15), newly diagnosed MM, (NDMM, n = 32), relapsed/refractory MM (RRMM, n = 19) and in 25 healthy controls by mass spectrometry.ResultsPatients with NDMM, RRMM and MGUS have a substantially different metabolomic profile than healthy controls. The amount of eight plasma metabolites significantly differs between the NDMM and MGUS group: free carnitine, acetylcarnitine, glutamate, asymmetric dimethylarginine (ADMA) and four phosphatidylcholine (PC) species. In addition, the levels of octadecanoylcarnitine, ADMA and six PCs were significantly different between RRMM and MGUS patients. 13 different concentrations of metabolites were found between RRMM and NDMM patients (free carnitine, acetylcarnitine, creatinine, five LysoPCs and PCs). Pathway analyses revealed a distinct metabolic profile with significant alterations in amino acid, lipid, and energy metabolism in healthy volunteers compared to MGUS/MM patients.ConclusionWe identified different metabolic profiles in MGUS und MM patients in comparison to healthy controls. Thus, different metabolic processes, potentially the immunoregulation by indoleamine 2,3 dioxygenase-1 (IDO), which is involved in cancer development and progression supporting inflammatory processes in the tumor microenvironment and glutaminolysis, can serve as novel promising therapeutic targets in MM.

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Alterations in bone marrow metabolism are an early and consistent feature during the development of MGUS and multiple myeloma

Cited by 22 publications

References 17 publications

Citrullination of histone H3 drives IL-6 production by bone marrow mesenchymal stem cells in MGUS and multiple myeloma

Citrullination of histone H3 drives IL-6 production by bone marrow mesenchymal stem cells in MGUS and multiple myeloma

Glutamine-derived 2-hydroxyglutarate is associated with disease progression in plasma cell malignancies

The metabolomic plasma profile of myeloma patients is considerably different from healthy subjects and reveals potential new therapeutic targets

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