Progression from Monoclonal gammopathy of undetermined significance of the immunoglobulin M class (IgM-MGUS) to Waldenstrom Macroglobulinemia is associated with an alteration in lipid metabolism

Shahrzad Jalali, Jie Shi, Nagib Ahsan, Linda E. Wellik, Ma Kayla Serres, Alex Buko, Jonas Paludo, Hyo Jin Kim, Xin Yi Tang, Zhi Zhang Yang, Anne J. Novak, Robert A. Kyle, Stephen M. Ansell

Research output: Contribution to journalArticlepeer-review

Abstract

The molecular events that modulate the progression of monoclonal gammopathy of undetermined significance of the immunoglobulin M class (IgM-MGUS) to Waldenstrom Macroglobulinemia (WM) are mostly unknown. We implemented comparative proteomics and metabolomics analyses on patient serum samples to identify differentially expressed molecules crucial to the progression from IgM-MGUS to WM. Our data identified altered lipid metabolism as a discriminating factor between MGUS, WM, and matched normal controls. Levels of many fatty acids, including polyunsaturated fatty acids and dicarboxylic acids, were significantly downregulated in WM sera when compared to MGUS. These reductions were associated with diminished 15-LOX and PPAR protein expression and increased 5-LOX and GPX4 expression in WM versus MGUS patients’ samples. Furthermore, WM serum samples showed increased lipid peroxidation compared to MGUS. Treatment with IL-6 or TNFα, upstream regulators of differentially expressed proteins between MGUS and WM, increased lipid absorption and lipid peroxidation in WM cell lines. Knock-down of 15-LOX expression increased WM cell survival, an effect accompanied by increased 5-LOX and GPX4 expression. In summary, our data show that reduced fatty acid and lipid metabolite levels in the serum of the WM patients are associated with increased lipid peroxidation and that downregulation of 15-LOX increases the survival of WM cells. These data are highly significant in identifying the biomarkers of disease progression and designing targeted therapeutic intervention.

Original languageEnglish (US)
Article number101927
JournalRedox Biology
Volume41
DOIs
StatePublished - May 2021

Keywords

  • Glutathione peroxidase
  • Lipid metabolism
  • Lipoxygenases
  • Metabolomics
  • Monoclonal gammopathy of undetermined significance of the immunoglobulin M class (IgM-MGUS)
  • Proteomics
  • Waldenstrom macroglobulinemia

ASJC Scopus subject areas

  • Organic Chemistry
  • Clinical Biochemistry

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