title: Aberrant O-GlcNAcylation characterizes chronic lymphocytic leukemia.
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.
authors.affiliation: Division of Molecular and Cellular Biology, Research Institute, Sunnybrook Health Sciences Center, Toronto, Ontario, Canada.
authors.forename: Y
authors.initials: Y
authors.lastname: Shi
authors.forename: J
authors.initials: J
authors.lastname: Tomic
authors.forename: F
authors.initials: F
authors.lastname: Wen
authors.forename: S
authors.initials: S
authors.lastname: Shaha
authors.forename: A
authors.initials: A
authors.lastname: Bahlo
authors.forename: R
authors.initials: R
authors.lastname: Harrison
authors.forename: J W
authors.initials: JW
authors.lastname: Dennis
authors.forename: R
authors.initials: R
authors.lastname: Williams
authors.forename: B J
authors.initials: BJ
authors.lastname: Gross
authors.forename: S
authors.initials: S
authors.lastname: Walker
authors.forename: J
authors.initials: J
authors.lastname: Zuccolo
authors.forename: J P
authors.initials: JP
authors.lastname: Deans
authors.forename: G W
authors.initials: GW
authors.lastname: Hart
authors.forename: D E
authors.initials: DE
authors.lastname: Spaner
mesh_terms: D000117:Acetylglucosamine / Q000378:metabolism*; D000215:Acylation; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D016207:Cytokines / Q000378:metabolism; D017931:DNA Primers; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D051193:Toll-Like Receptors / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D016207:Cytokines; D017931:DNA Primers; D051193:Toll-Like Receptors; D000117:Acetylglucosamine