Department of Biochemistry and Molecular Biology and Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, 533 Bolivar Street, New Orleans, LA 70112, USA.
Mol Cell Endocrinol. 2010 May 14;320(1-2):76-86. doi: 10.1016/j.mce.2010.02.014. Epub 2010 Feb 17.
Glucocorticoids (GCs) are used in combination therapy for treating acute lymphoblastic leukemia (ALL). In T-cell (CEM-C7) and pre-B-cell (697) ALL cell lines, dexamethasone (Dex) treatment causes an auto-upregulation of glucocorticoid receptor (GR) mRNA transcripts and protein. We hypothesized that there is a threshold level of GR transcripts/protein needed for cells to respond to the apoptosis-inducing effects of hormone. GR knock down using a doxycycline-controllable shRNAmir indicated that the apoptotic response changes from sensitive to resistant with changing GR levels. Titration of the 697 cell GR to equal that of the CEM-C7 T-cell ALL line caused a shift in sensitivity to that seen in CEM-C7 cells. While the same level of GR is required to trigger apoptosis in both T-cell and pre-B-cell ALL lineages, similarities and differences were observed for the regulation of target genes in these lineages. These preliminary gene regulation patterns may lead to the development of a molecular signature for GC-sensitive and GC-resistant leukemia cells.
糖皮质激素（GCs）被用于联合治疗急性淋巴细胞白血病（ALL）。在 T 细胞（CEM-C7）和前 B 细胞（697）ALL 细胞系中，地塞米松（Dex）治疗导致糖皮质激素受体（GR）mRNA 转录本和蛋白的自动上调。我们假设，细胞需要达到一定水平的 GR 转录本/蛋白，才能对激素的诱导凋亡作用产生反应。使用可由多西环素控制的 shRNAmir 敲低 GR 表明，随着 GR 水平的变化，凋亡反应从敏感变为耐药。将 697 细胞的 GR 滴定至与 CEM-C7 T 细胞 ALL 系相等，导致敏感性发生变化，与 CEM-C7 细胞相似。虽然两种 T 细胞和前 B 细胞 ALL 谱系都需要相同水平的 GR 来触发凋亡，但在这些谱系中，靶基因的调控存在相似和不同之处。这些初步的基因调控模式可能会导致开发出用于 GC 敏感和 GC 耐药白血病细胞的分子特征。
