Elevated Choline Kinase α-Mediated Choline Metabolism Supports the Prolonged Survival of TRAF3-Deficient B Lymphocytes

J Immunol. 2020 Jan 15;204(2):459-471. doi: 10.4049/jimmunol.1900658. Epub 2019 Dec 11.


Specific deletion of the tumor suppressor TRAF3 from B lymphocytes in mice leads to the prolonged survival of mature B cells and expanded B cell compartments in secondary lymphoid organs. In the current study, we investigated the metabolic basis of TRAF3-mediated regulation of B cell survival by employing metabolomic, lipidomic, and transcriptomic analyses. We compared the polar metabolites, lipids, and metabolic enzymes of resting splenic B cells purified from young adult B cell-specific Traf3 -/- and littermate control mice. We found that multiple metabolites, lipids, and enzymes regulated by TRAF3 in B cells are clustered in the choline metabolic pathway. Using stable isotope labeling, we demonstrated that phosphocholine and phosphatidylcholine biosynthesis was markedly elevated in Traf3 -/- mouse B cells and decreased in TRAF3-reconstituted human multiple myeloma cells. Furthermore, pharmacological inhibition of choline kinase α, an enzyme that catalyzes phosphocholine synthesis and was strikingly increased in Traf3 -/- B cells, substantially reversed the survival phenotype of Traf3 -/- B cells both in vitro and in vivo. Taken together, our results indicate that enhanced phosphocholine and phosphatidylcholine synthesis supports the prolonged survival of Traf3 -/- B lymphocytes. Our findings suggest that TRAF3-regulated choline metabolism has diagnostic and therapeutic value for B cell malignancies with TRAF3 deletions or relevant mutations.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • B-Lymphocytes / physiology*
  • Cell Line
  • Cell Survival
  • Choline / metabolism*
  • Choline Kinase / genetics
  • Choline Kinase / metabolism*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Mice
  • Mice, Knockout
  • Multiple Myeloma / genetics
  • Multiple Myeloma / metabolism*
  • Multiple Myeloma / pathology
  • Mutation / genetics
  • Phosphorylcholine / metabolism
  • Signal Transduction
  • TNF Receptor-Associated Factor 3 / genetics
  • TNF Receptor-Associated Factor 3 / metabolism*


  • TNF Receptor-Associated Factor 3
  • Phosphorylcholine
  • Chka protein, mouse
  • Choline Kinase
  • Choline