Haploinsufficiency of C2GnT-I glycosyltransferase renders T lymphoma cells resistant to cell death.

Abstract

Neoplastic T cells in mycosis fungoides (MF) are resistant to apoptotic agents, including galectin-1 that is abundant in skin. Although MF cells are typically CD7-, and thus galectin-1 resistant, CD7+ HH cells, derived from a patient with MF, were also resistant to galectin-1. HH cells demonstrate altered cell surface glycosylation, with loss of core 2 O-glycan ligands for galectin-1 created by core 2 beta1,6-N-acetylglucosaminyltransferase (C2GnT-I). Loss of core 2 O-glycans on tumor cells was also seen in primary CD7+ MF lesions. Surprisingly, HH cells are heterozygous for a C2GnT-I point mutation, yet this mutation resulted in a dramatic reduction in cellular glycosyltransferase activity. Expression of wild-type C2GnT-I in human HH cells, or murine lymphoma cells that lack C2GnT-I, restored core 2 O-glycan expression and susceptibility to galectin-1, whereas mutant enzyme lacked activity and did not restore core 2 O-glycan expression or susceptibility to galectin-1. Mutant enzyme did not have a dominant negative effect by affecting dimerization or activity of wild-type enzyme; rather, C2GnT-I haploinsufficiency is sufficient for loss of core 2 O-glycan expression and galectin-1 resistance. Thus, glycosyltransferase haploinsufficiency results in altered cellular glycosylation and resistance to cell death, identifying a new survival mechanism for T-lymphoma cells.

• Authors: Paula V Cabrera, Maho Amano, Junya Mitoma, Jessica Chan, Jonathan Said, Minoru Fukuda, Linda G Baum
• Journal: Blood (Blood) Vol. 108 Issue 7 Pg. 2399-406 (Oct 01 2006) ISSN: 0006-4971 [Print] United States
• PMID: 16778138 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antigens, CD7
• Galectin 1
• N-Acetylglucosaminyltransferases
• beta-1,3-galactosyl-O-glycosyl-glycoprotein beta-1,6-acetylglucosaminyl transferase

Topics

• Antigens, CD7 (biosynthesis)
• Apoptosis
• Base Sequence
• Cell Line, Tumor
• Cell Survival
• Galectin 1 (chemistry)
• Genetic Predisposition to Disease
• Heterozygote
• Humans
• Lymphoma, T-Cell (enzymology, genetics, pathology)
• Molecular Sequence Data
• Mutation, Missense
• N-Acetylglucosaminyltransferases (genetics, physiology)
• Skin (metabolism)