Low glucocorticoid receptor α/β ratio in T-cell lymphoblastic leukemia
Low glucocorticoid receptor α/β ratio in T-cell lymphoblastic leukemia
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DOI：
10.1055/s-2007-978661
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发表时间：
2000-10-01
影响因子：
2.2
通讯作者：
Chrousos, GP
中科院分区：
文献类型：
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作者：
Longui, CA;Vottero, A;Chrousos, GP
糖皮质激素治疗是急性淋巴细胞性白血病(ALL)治疗的关键，它抑制细胞增殖，促进细胞周期停滞，并通过细胞凋亡诱导细胞死亡，白血病细胞对糖皮质激素的敏感性以前与(3)[H]地塞米松结合部位的细胞浓度有关。后者代表经典的糖皮质激素受体(GR)亚型cr，它结合配体并调节糖皮质激素反应基因的转录速率。总体而言，T系淋巴母细胞对糖皮质激素的敏感性低于B系细胞，选择性剪接CR异构体(GRβ)对GRα介导的转录活性具有明显的负效应，已被认为可能是糖皮质激素抵抗的媒介。在这项研究中，我们用定量的Western分析方法检测了13例初诊和未治疗的ALL患儿和9例对照组的单个核细胞中GRα和GRβ的含量。一般来说，白血病患者GRα的表达比对照组少6倍(ALL=0.54+/-1.1；对照组=3.1+/-0.9；P<；0.01)，但GRP的量相同(ALL=3.62+/-3.3：对照组=3.6+/-3.4)。所有T细胞病患者的GR表达均显著低于对照组(0.09+/-0.1；P<；0.01)，但GR表达相似或略高(5.98+/-3.9：P=0.1)，GRα/GRβ比值小于对照组的15倍。与Pre-B免疫表型细胞相比，T细胞系的单核白细胞表达的GRα显著降低(p=0.04)，CRβ显著升高(p<；0.01)，比率降低10倍。我们的结论是：白血病淋巴母细胞低GR和正常到高GRβ表达的组合可能是导致其对糖皮质激素敏感性降低的机制之一；这在T系细胞中更为明显。
Glucocorticoid therapy is pivotal in the treatment of acute lymphoblastic leukemia (ALL); it reduces cell proliferation, promotes cell cycle arrest, and induces cell death by apoptosis, The sensitivity of leukemic cells to glucocorticoids was previously related to the cell concentration of (3)[H]dexamethasone-binding sites. The latter represents the classic glucocorticoid receptor (GR) isoform cr that binds ligand and modulates the transcription rates of glucocorticoid-responsive genes. In ALL, lymphoblasts of T-lineage are less sensitive to glucocorticoids than cells of the B-lineage, The alternatively spliced CR isoform (GR beta), which exerts a dominant negative effect on GR alpha -mediated transcriptional activity, has been proposed as a possible mediator of glucocorticoid resistance. In this study, we determined the amount of GR alpha and GR beta in mononuclear cells from 13 newly diagnosed and untreated children with ALL and 9 controls by quantitative Western analysis. Generally, leukemic patients expressed 6 times less GR alpha (ALL = 0.54 +/- 1.1; controls = 3.1 +/- 0.9; p < 0.01) than controls, but the same amount of GRP (ALL = 3.62 +/- 3.3: controls = 3.6 +/- 3.4). ALL patients with T-cell disease had a much lower GR (0.09 +/- 0.1;p < 0.01) but a similar or slightly higher GR (5.98 +/- 3.9: p = 0.1) expression than controls, with a GR alpha /GR beta ratio 15 times smaller than controls. Mononuclear leukocytes of T-cell lineage expressed significantly lower GR alpha (p = 0.04) and higher CR beta (p < 0.01) than cells of the pre-B immunophenotype, with a 10 times smaller ratio. We conclude that: the combination of low GR and normal-to-high GR beta expression in leukemic lymphoblasts might represent one of the mechanisms responsible for their reduced glucocorticoid sensitivity; this is more pronounced in T-lineage cells.