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Blood, 1 October 2006, Vol. 108, No. 7, pp. 2399-2406.
Prepublished online as a Blood First Edition Paper on June 15, 2006; DOI 10.1182/blood-2006-04-018556.
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Submitted April 20, 2006
Accepted May 27, 2006
Haploinsufficiency of C2GnT-I glycosyltransferase renders T lymphoma cells resistant to cell death
Paula V Cabrera, Maho Amano, Junya Mitoma, Jessica Chan, Jonathan Said, Minoru Fukuda, and Linda G Baum*
Department of Pathology & Jonsson Comprehensive Cancer Center, University of California, Los Angeles
Glycobiology Program, Cancer Research Center, Burnham Institute, La Jolla, CA, USA
* Corresponding author; email: lbaum{at}mednet.ucla.edu.
Neoplastic T cells in mycosis fungoides (MF) are resistant to apoptotic agents, including galectin-1 that is abundant in skin. While MF cells are typically CD7-, and thus galectin-1 resistant, CD7+ HH cells, derived from an MF patient, 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  1,6-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 wildtype 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, while 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 wildtype 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.
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