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Updated: Jul 9, 2026
Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
Published on: January 22, 2019
Gene expression profiling of leukemic cells and primary thymocytes predicts a signature for apoptotic sensitivity to
Aaron L Miller1, Spogmai Komak, M Scott Webb
1Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, TX, USA. aamiller@utmb.edu
Background:
Glucocorticoids (GC's) play an integral role in treatment strategies designed to combat various forms of hematological malignancies. GCs also are powerful inhibitors of the immune system, through regulation of appropriate cytokines and by causing apoptosis of immature thymocytes. By activating the glucocorticoid receptor (GR), GCs evoke apoptosis through transcriptional regulation of a complex, interactive gene network over a period of time preceding activation of the apoptotic enzymes. In this study we used microarray technology to determine whether several disparate types of hematologic cells, all sensitive to GC-evoked apoptosis, would identify a common set of regulated genes. We compared gene expression signatures after treatment with two potent synthetic GCs, dexamethasone (Dex) and cortivazol (CVZ) using a panel of hematologic cells. Pediatric CD4+/CD8+ T-cell leukemia was represented by 3 CEM clones: two sensitive, CEM-C7-14 and CEM-C1-6, and one resistant, CEM-C1-15, to Dex. CEM-C1-15 was also tested when rendered GC-sensitive by several treatments. GC-sensitive pediatric B-cell leukemia was represented by the SUP-B15 line and adult B-cell leukemia by RS4;11 cells. Kasumi-1 cells gave an example of the rare Dex-sensitive acute myeloblastic leukemia (AML). To test the generality of the correlations in malignant cell gene sets, we compared with GC effects on mouse non-transformed thymocytes.
Results:
We identified a set of genes regulated by GCs in all GC-sensitive malignant cells. A portion of these were also regulated in the thymocytes. Because we knew that the highly Dex-resistant CEM-C1-15 cells could be killed by CVZ, we tested these cells with the latter steroid and again found that many of the same genes were now regulated as in the inherently GC-sensitive cells. The same result was obtained when we converted the Dex-resistant clone to Dex-sensitive by treatment with forskolin (FSK), to activate the adenyl cyclase/protein kinase A pathway (PKA).
Conclusion:
Our results have identified small sets of genes that correlate with GC-sensitivity in cells from several hematologic malignancies. Some of these are also regulated in normal mouse thymocytes.
Insights
Glucocorticoids (GCs) induce apoptosis in hematologic malignancy cells by regulating specific genes. This study identified common gene sets linked to GC sensitivity across various leukemia types, offering insights into GC therapy.
Area of Science:
- Molecular Biology
- Cancer Research
- Immunology
Background:
- Glucocorticoids (GCs) are crucial in treating hematological malignancies and suppressing the immune system via apoptosis.
- GCs activate the glucocorticoid receptor (GR), initiating a gene network that leads to apoptosis.
- Understanding GC-regulated genes is key to optimizing cancer therapy.
Purpose of the Study:
- To identify common gene expression signatures regulated by GCs in diverse, GC-sensitive hematologic cells.
- To compare GC effects on malignant cells with those on normal mouse thymocytes.
- To investigate gene regulation in GC-resistant cells upon restoration of sensitivity.
Main Methods:
- Utilized microarray technology to analyze gene expression profiles.
- Treated various hematologic cell lines (leukemia, AML) and mouse thymocytes with synthetic GCs (dexamethasone, cortivazol).
- Assessed GC sensitivity modulation using forskolin (FSK) to activate the protein kinase A (PKA) pathway.
Main Results:
- Identified a core set of genes regulated by GCs in all tested GC-sensitive malignant hematologic cells.
- Observed overlap in regulated genes between malignant cells and normal mouse thymocytes.
- Found that GC-resistant cells (CEM-C1-15) exhibited similar gene regulation patterns when treated with cortivazol or rendered sensitive via FSK/PKA activation.
Conclusions:
- Pinpointed small gene sets that correlate with GC sensitivity in various hematologic malignancies.
- These key gene sets are also regulated in normal mouse thymocytes, suggesting conserved mechanisms.
- Findings provide a foundation for understanding GC resistance and developing targeted therapies.
