Aberrant O-GlcNAcylation characterizes chronic lymphocytic leukemia

Y. Shi, J. Tomic, F. Wen, S. Shaha, A. Bahlo, R. Harrison, J. W. Dennis, R. Williams, B. J. Gross, S. Walker, J. Zuccolo, J. P. Deans, Gerald Warren Hart, D. E. Spaner

Research output: Contribution to journalArticlepeer-review

Abstract

O-linked N-Acetylglucosamine (O-GlcNAc) post-translational modifications originate from the activity of the hexosamine pathway, and are known to affect intracellular signaling processes. As aberrant responses to microenvironmental signals are a feature of chronic lymphocytic leukemia (CLL), O-GlcNAcylated protein levels were measured in primary CLL cells. In contrast to normal circulating and tonsillar B cells, CLL cells expressed high levels of O-GlcNAcylated proteins, including p53, c-myc and Akt. O-GlcNAcylation in CLL cells increased following activation with cytokines and through toll-like receptors (TLRs), or after loading with hexosamine pathway substrates. However, high baseline O-GlcNAc levels were associated with impaired signaling responses to TLR agonists, chemotherapeutic agents, B cell receptor crosslinking and mitogens. Indolent and aggressive clinical behavior of CLL cells were found to correlate with higher and lower O-GlcNAc levels, respectively. These findings suggest that intracellular O-GlcNAcylation is associated with the pathogenesis of CLL, which could potentially have therapeutic implications.

Original languageEnglish (US)
Pages (from-to)1588-1598
Number of pages11
JournalLeukemia
Volume24
Issue number9
DOIs
StatePublished - Sep 2010

Keywords

  • chronic lymphocytic leukemia
  • glucosamine
  • glycolysis
  • hexosamine pathway
  • signal transduction

ASJC Scopus subject areas

  • Hematology
  • Cancer Research
  • Anesthesiology and Pain Medicine
  • Medicine(all)

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