Haploinsufficiency of C2GnT-I glycosyltransferase renders T lymphoma cells resistant to cell death
Haploinsufficiency of C2GnT-I glycosyltransferase renders T lymphoma cells resistant to cell death
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DOI：
10.1182/blood-2006-04-018556
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发表时间：
2006-10-01
期刊：
影响因子：
20.3
通讯作者：
Baum, Linda G.
中科院分区：
文献类型：
--
作者：
Cabrera, Paula V.;Amano, Maho;Baum, Linda G.
蕈样肉芽肿（MF）中的肿瘤性T细胞对凋亡剂具有抗性，包括皮肤中丰富的半乳糖凝集素-1。虽然MF细胞通常是CB 7（-），因此具有半乳糖凝集素-1抗性，但来自MF患者的CD 7（+）HH细胞也对半乳糖凝集素-1具有抗性。HH细胞表现出改变的细胞表面糖基化，丧失了由核心2 β 1，6-N-乙酰葡糖胺转移酶（C2 GnT-I）产生的半乳糖凝集素-1的核心2 β 1聚糖配体。在原发性CD 7 + MF病变中也观察到肿瘤细胞上核心2 O-聚糖的丢失。令人惊讶的是，HH细胞对于C2 GnT-I点突变是杂合的，然而该突变导致细胞糖基转移酶活性的显著降低。野生型C2 GnT-I在人HH细胞或缺乏C2 GnT-I的鼠淋巴瘤细胞中的表达恢复了核心2 O-聚糖表达和对半乳糖凝集素-1的易感性，而突变酶缺乏活性并且没有恢复核心2 O-聚糖表达或对半乳糖凝集素-1的易感性。突变酶通过影响野生型酶的二聚化或活性而不具有显性负效应;相反，C2 GnT-I单倍不足足以导致核心2 O-聚糖表达和半乳糖凝集素-1抗性的丧失。因此，糖基转移酶单倍不足导致改变的细胞糖基化和对细胞死亡的抗性，确定了T淋巴瘤细胞的新存活机制。
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 CB7(-), 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 01 glycan ligands for galectin-1 created by core 2 beta 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 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.