Haploinsufficiency of C2GnT-I glycosyltransferase renders T lymphoma cells resistant to cell death.
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.
Cabrera
Paula V
PV
Department of Pathology, UCLA School of Medicine, 10833 Le Conte Ave, Los Angeles, CA 90095-1732, USA.
Amano
Maho
M
Mitoma
Junya
J
Chan
Jessica
J
Said
Jonathan
J
Fukuda
Minoru
M
Baum
Linda G
LG
D019011:Antigens, CD7 / Q000096:biosynthesis; D017209:Apoptosis; D001483:Base Sequence; D045744:Cell Line, Tumor; D002470:Cell Survival; D037483:Galectin 1 / Q000737:chemistry; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D016399:Lymphoma, T-Cell / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics* / Q000502:physiology*; D012867:Skin / Q000378:metabolism
D019011:Antigens, CD7; D037483:Galectin 1; D017351:N-Acetylglucosaminyltransferases; C053024:beta-1,3-galactosyl-O-glycosyl-glycoprotein beta-1,6-acetylglucosaminyl transferase