Aberrant O-GlcNAcylation characterizes chronic lymphocytic leukemia.
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.
Shi
Y
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Division of Molecular and Cellular Biology, Research Institute, Sunnybrook Health Sciences Center, Toronto, Ontario, Canada.
Tomic
J
J
Wen
F
F
Shaha
S
S
Bahlo
A
A
Harrison
R
R
Dennis
J W
JW
Williams
R
R
Gross
B J
BJ
Walker
S
S
Zuccolo
J
J
Deans
J P
JP
Hart
G W
GW
Spaner
D E
DE
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
D016207:Cytokines; D017931:DNA Primers; D051193:Toll-Like Receptors; D000117:Acetylglucosamine