Glucocorticoid receptor knock down reveals a similar apoptotic threshold but differing gene regulation patterns in T-cell and pre-B-cell acute lymphoblastic leukemia

• Published in: Molecular and cellular endocrinology 2010-05, Vol.320 (1), p.76-86
• Main Authors: Schwartz, Jason R., Sarvaiya, Purvaba J., Vedeckis, Wayne V.
• Format: Article
• Language: English
• Subjects: Acute lymphoblastic leukemia; Apoptosis; Apoptosis - drug effects; Auto-regulation; Cell Cycle - drug effects; Cell Line, Tumor; Dexamethasone - pharmacology; Doxycycline - pharmacology; Drug Resistance, Neoplasm - drug effects; Gene Expression Regulation, Leukemic - drug effects; Gene Knockdown Techniques; Glucocorticoid receptor; Humans; Intracellular Space - drug effects; Intracellular Space - metabolism; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - pathology; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - pathology; Receptors, Glucocorticoid - genetics; Receptors, Glucocorticoid - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA, Small Interfering - metabolism; Threshold; Titrimetry
• ISSN: 0303-7207; 1872-8057
• DOI: 10.1016/j.mce.2010.02.014

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.