{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T05:54:29Z","timestamp":1794030869594,"version":"4.8.0"},"reference-count":31,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,6,24]],"date-time":"2020-06-24T00:00:00Z","timestamp":1592956800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,6,24]],"date-time":"2020-06-24T00:00:00Z","timestamp":1592956800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Oncogenic drivers of progression of monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM) such as c-MYC have downstream effects on intracellular metabolic pathways of clonal plasma cells (PCs). Thus, extracellular environments such as the bone marrow (BM) plasma likely have unique metabolite profiles that differ from patients with MGUS compared to MM. This study utilized an untargeted metabolite and targeted complex lipid profiling of BM plasma to identify significant differences in the relative metabolite levels between patients with MGUS and MM from an exploratory cohort. This was followed by verification of some of the metabolite differences of interest by targeted quantification of the metabolites using isotopic internal standards in the exploratory cohort as well as an independent validation cohort. Significant differences were noted in the amino acid profiles such as decreased branch chain amino acids (BCAAs) and increased catabolism of tryptophan to the active kynurenine metabolite 3-hydroxy-kynurenine between patients with MGUS and MM. A decrease in the total levels of complex lipids such as phosphatidylethanolamines (PE), lactosylceramides (LCER) and phosphatidylinositols (PI) were also detected in the BM plasma samples from MM compared to MGUS patients. Thus, metabolite and complex lipid profiling of the BM plasma identifies differences in levels of metabolites and lipids between patients with MGUS and MM. This may provide insight into the possible differences of the intracellular metabolic pathways of their clonal PCs.<\/jats:p>","DOI":"10.1038\/s41598-020-67105-3","type":"journal-article","created":{"date-parts":[[2020,6,24]],"date-time":"2020-06-24T10:02:52Z","timestamp":1592992972000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":45,"title":["Metabolomic and Lipidomic Profiling of Bone Marrow Plasma Differentiates Patients with Monoclonal Gammopathy of Undetermined Significance from Multiple Myeloma"],"prefix":"10.1038","volume":"10","author":[{"given":"Wilson I.","family":"Gonsalves","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katarzyna","family":"Broniowska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik","family":"Jessen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuan-Mai","family":"Petterson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander Graham","family":"Bush","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaimee","family":"Gransee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martha Q.","family":"Lacy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taro","family":"Hitosugi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaji K.","family":"Kumar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,6,24]]},"reference":[{"key":"67105_CR1","doi-asserted-by":"publisher","first-page":"17046","DOI":"10.1038\/nrdp.2017.46","volume":"3","author":"SK Kumar","year":"2017","unstructured":"Kumar, S. K. et al. Multiple myeloma. Nat Rev Dis Primers. 3, 17046 (2017).","journal-title":"Nat Rev Dis Primers."},{"issue":"22","key":"67105_CR2","doi-asserted-by":"publisher","first-page":"5412","DOI":"10.1182\/blood-2008-12-194241","volume":"113","author":"O Landgren","year":"2009","unstructured":"Landgren, O. et al. Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study. Blood. 113(22), 5412\u20137 (2009).","journal-title":"Blood."},{"issue":"2","key":"67105_CR3","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1182\/blood-2017-09-807560","volume":"131","author":"RS Go","year":"2018","unstructured":"Go, R. S. & Rajkumar, S. V. How I manage monoclonal gammopathy of undetermined significance. Blood. 131(2), 163\u201373 (2018).","journal-title":"Blood."},{"key":"67105_CR4","doi-asserted-by":"crossref","unstructured":"Misund, K. et al. MYC dysregulation in the progression of multiple myeloma. Leukemia. (2019).","DOI":"10.1038\/s41375-019-0543-4"},{"issue":"9","key":"67105_CR5","doi-asserted-by":"publisher","first-page":"877","DOI":"10.1101\/gad.189365.112","volume":"26","author":"CV Dang","year":"2012","unstructured":"Dang, C. V. Links between metabolism and cancer. Genes Dev. 26(9), 877\u201390 (2012).","journal-title":"Genes Dev."},{"issue":"1","key":"67105_CR6","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/j.cmet.2015.12.006","volume":"23","author":"NN Pavlova","year":"2016","unstructured":"Pavlova, N. N. & Thompson, C. B. The Emerging Hallmarks of Cancer Metabolism. Cell Metab. 23(1), 27\u201347 (2016).","journal-title":"Cell Metab."},{"key":"67105_CR7","doi-asserted-by":"crossref","unstructured":"Gonsalves WI, et al. Glutamine-derived 2-hydroxyglutarate is associated with disease progression in plasma cell malignancies. JCI Insight. 3(1) (2018).","DOI":"10.1172\/jci.insight.94543"},{"issue":"6","key":"67105_CR8","doi-asserted-by":"publisher","first-page":"1026","DOI":"10.1038\/leu.2011.53","volume":"25","author":"WJ Chng","year":"2011","unstructured":"Chng, W. J. et al. Clinical and biological implications of MYC activation: a common difference between MGUS and newly diagnosed multiple myeloma. Leukemia. 25(6), 1026\u201335 (2011).","journal-title":"Leukemia."},{"issue":"3","key":"67105_CR9","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1007\/s11306-014-0721-3","volume":"11","author":"MK Aurich","year":"2015","unstructured":"Aurich, M. K. et al. Prediction of intracellular metabolic states from extracellular metabolomic data. Metabolomics. 11(3), 603\u201319 (2015).","journal-title":"Metabolomics."},{"key":"67105_CR10","doi-asserted-by":"publisher","DOI":"10.1038\/bcj.2015.85","volume":"5","author":"C Ludwig","year":"2015","unstructured":"Ludwig, C. et al. Alterations in bone marrow metabolism are an early and consistent feature during the development of MGUS and multiple myeloma. Blood Cancer J. 5, e359 (2015).","journal-title":"Blood Cancer J."},{"issue":"8","key":"67105_CR11","doi-asserted-by":"publisher","first-page":"e0202045","DOI":"10.1371\/journal.pone.0202045","volume":"13","author":"N Steiner","year":"2018","unstructured":"Steiner, N. et al. The metabolomic plasma profile of myeloma patients is considerably different from healthy subjects and reveals potential new therapeutic targets. PLoS One. 13(8), e0202045 (2018).","journal-title":"PLoS One."},{"issue":"17","key":"67105_CR12","doi-asserted-by":"publisher","first-page":"4770","DOI":"10.1158\/1078-0432.CCR-12-2917","volume":"19","author":"L Puchades-Carrasco","year":"2013","unstructured":"Puchades-Carrasco, L. et al. Multiple myeloma patients have a specific serum metabolomic profile that changes after achieving complete remission. Clin Cancer Res. 19(17), 4770\u20139 (2013).","journal-title":"Clin Cancer Res."},{"issue":"2","key":"67105_CR13","doi-asserted-by":"publisher","first-page":"e56422","DOI":"10.1371\/journal.pone.0056422","volume":"8","author":"A Lodi","year":"2013","unstructured":"Lodi, A. et al. Proton NMR-based metabolite analyses of archived serial paired serum and urine samples from myeloma patients at different stages of disease activity identifies acetylcarnitine as a novel marker of active disease. PLoS One. 8(2), e56422 (2013).","journal-title":"PLoS One."},{"key":"67105_CR14","doi-asserted-by":"publisher","first-page":"884","DOI":"10.3389\/fphar.2018.00884","volume":"9","author":"H Du","year":"2018","unstructured":"Du, H. et al. Analysis of the Metabolic Characteristics of Serum Samples in Patients With Multiple Myeloma. Front Pharmacol. 9, 884 (2018).","journal-title":"Front Pharmacol."},{"issue":"8","key":"67105_CR15","doi-asserted-by":"publisher","first-page":"1158","DOI":"10.1373\/clinchem.2018.287045","volume":"64","author":"JA Kirwan","year":"2018","unstructured":"Kirwan, J. A. et al. Preanalytical Processing and Biobanking Procedures of Biological Samples for Metabolomics Research: A White Paper, Community Perspective (for \u201cPrecision Medicine and Pharmacometabolomics Task Group\u201d-The Metabolomics Society Initiative). Clin Chem. 64(8), 1158\u201382 (2018).","journal-title":"Clin Chem."},{"issue":"10","key":"67105_CR16","doi-asserted-by":"publisher","first-page":"1269","DOI":"10.1038\/nm934","volume":"9","author":"C Uyttenhove","year":"2003","unstructured":"Uyttenhove, C. et al. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat Med. 9(10), 1269\u201374 (2003).","journal-title":"Nat Med."},{"issue":"3","key":"67105_CR17","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1016\/j.ygyno.2010.02.028","volume":"117","author":"T Inaba","year":"2010","unstructured":"Inaba, T. et al. Indoleamine 2,3-dioxygenase expression predicts impaired survival of invasive cervical cancer patients treated with radical hysterectomy. Gynecol Oncol. 117(3), 423\u20138 (2010).","journal-title":"Gynecol Oncol."},{"issue":"17-18","key":"67105_CR18","doi-asserted-by":"publisher","first-page":"1236","DOI":"10.1101\/gad.327056.119","volume":"33","author":"N Venkateswaran","year":"2019","unstructured":"Venkateswaran, N. et al. MYC promotes tryptophan uptake and metabolism by the kynurenine pathway in colon cancer. Genes Dev. 33(17-18), 1236\u201351 (2019).","journal-title":"Genes Dev."},{"issue":"5","key":"67105_CR19","doi-asserted-by":"publisher","first-page":"850","DOI":"10.1038\/s41591-019-0404-8","volume":"25","author":"H Li","year":"2019","unstructured":"Li, H. et al. The landscape of cancer cell line metabolism. Nat Med. 25(5), 850\u201360 (2019).","journal-title":"Nat Med."},{"issue":"11","key":"67105_CR20","first-page":"765","volume":"31","author":"T Motyl","year":"1993","unstructured":"Motyl, T. et al. Blood plasma pseudouridine in patients with malignant proliferative diseases. Eur J Clin Chem Clin Biochem. 31(11), 765\u201371 (1993).","journal-title":"Eur J Clin Chem Clin Biochem."},{"issue":"11","key":"67105_CR21","doi-asserted-by":"publisher","first-page":"2426","DOI":"10.1038\/leu.2017.102","volume":"31","author":"SV Glavey","year":"2017","unstructured":"Glavey, S. V. et al. Proteomic characterization of human multiple myeloma bone marrow extracellular matrix. Leukemia. 31(11), 2426\u201334 (2017).","journal-title":"Leukemia."},{"issue":"12","key":"67105_CR22","doi-asserted-by":"publisher","first-page":"e538","DOI":"10.1016\/S1470-2045(14)70442-5","volume":"15","author":"SV Rajkumar","year":"2014","unstructured":"Rajkumar, S. V. et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 15(12), e538\u201348 (2014).","journal-title":"Lancet Oncol."},{"issue":"20","key":"67105_CR23","doi-asserted-by":"publisher","first-page":"3069","DOI":"10.1182\/blood-2014-09-568899","volume":"125","author":"SV Rajkumar","year":"2015","unstructured":"Rajkumar, S. V., Landgren, O. & Mateos, M. V. Smoldering multiple myeloma. Blood. 125(20), 3069\u201375 (2015).","journal-title":"Blood."},{"issue":"16","key":"67105_CR24","doi-asserted-by":"publisher","first-page":"6656","DOI":"10.1021\/ac901536h","volume":"81","author":"AM Evans","year":"2009","unstructured":"Evans, A. M., DeHaven, C. D., Barrett, T., Mitchell, M. & Milgram, E. Integrated, nontargeted ultrahigh performance liquid chromatography\/electrospray ionization tandem mass spectrometry platform for the identification and relative quantification of the small-molecule complement of biological systems. Anal Chem. 81(16), 6656\u201367 (2009).","journal-title":"Anal Chem."},{"key":"67105_CR25","unstructured":"Evans, A. M. et al. High Resolution Mass Spectrometry Improves Data Quantity and Quality as Compared to Unit Mass Resolution Mass Spectrometry in HighThroughput Profiling Metabolomics. Metabolomics: Open Access. 4(2) (2014)."},{"issue":"1","key":"67105_CR26","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1186\/1758-2946-2-9","volume":"2","author":"CD Dehaven","year":"2010","unstructured":"Dehaven, C. D., Evans, A. M., Dai, H. & Lawton, K. A. Organization of GC\/MS and LC\/MS metabolomics data into chemical libraries. J Cheminform. 2(1), 9 (2010).","journal-title":"J Cheminform."},{"issue":"1","key":"67105_CR27","doi-asserted-by":"publisher","first-page":"e86","DOI":"10.1002\/cpbi.86","volume":"68","author":"J Chong","year":"2019","unstructured":"Chong, J., Wishart, D. S. & Xia, J. Using MetaboAnalyst 4.0 for Comprehensive and Integrative Metabolomics Data Analysis. Curr Protoc Bioinformatics. 68(1), e86 (2019).","journal-title":"Curr Protoc Bioinformatics."},{"issue":"3","key":"67105_CR28","doi-asserted-by":"publisher","first-page":"376","DOI":"10.20411\/pai.v2i3.218","volume":"2","author":"MA Belury","year":"2017","unstructured":"Belury, M. A. et al. Prospective Analysis of Lipid Composition Changes with Antiretroviral Therapy and Immune Activation in Persons Living with HIV. Pathog Immun. 2(3), 376\u2013403 (2017).","journal-title":"Pathog Immun."},{"issue":"5","key":"67105_CR29","doi-asserted-by":"publisher","first-page":"e10538","DOI":"10.1371\/journal.pone.0010538","volume":"5","author":"IR Lanza","year":"2010","unstructured":"Lanza, I. R. et al. Quantitative metabolomics by H-NMR and LC-MS\/MS confirms altered metabolic pathways in diabetes. PLoS One. 5(5), e10538 (2010).","journal-title":"PLoS One."},{"issue":"16","key":"67105_CR30","doi-asserted-by":"publisher","first-page":"9440","DOI":"10.1073\/pnas.1530509100","volume":"100","author":"JD Storey","year":"2003","unstructured":"Storey, J. D. & Tibshirani, R. Statistical significance for genomewide studies. Proc Natl Acad Sci USA 100(16), 9440\u20135 (2003).","journal-title":"Proc Natl Acad Sci USA"},{"key":"67105_CR31","doi-asserted-by":"publisher","first-page":"205","DOI":"10.4236\/ojs.2011.13024","volume":"1","author":"MW Mitchel","year":"2011","unstructured":"Mitchel, M. W. Bias of the Random Forest Out-of-Bag (OOB) Error for Certain Input Parameters. Open Journal of Statistics. 1, 205\u201311 (2011).","journal-title":"Open Journal of Statistics."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-67105-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-67105-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-67105-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,6]],"date-time":"2022-12-06T12:23:25Z","timestamp":1670329405000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-67105-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,6,24]]},"references-count":31,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["67105"],"URL":"https:\/\/doi.org\/10.1038\/s41598-020-67105-3","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,6,24]]},"assertion":[{"value":"4 March 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 June 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 June 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"10250"}}