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A Chromatin Immunoprecipitation Assay to Identify Novel NFAT2 Target Genes in Chronic Lymphocytic Leukemia
Published on: December 4, 2018
Genomewide identification of prednisolone-responsive genes in acute lymphoblastic leukemia cells
Wim J E Tissing1, Monique L den Boer, Jules P P Meijerink
1Department of Pediatric Oncology/Hematology, Erasmus MC/Sophia Children's Hospital, Dr Molewaterplein 60, 3015 GJ Rotterdam, The Netherlands.
Abstract:
Glucocorticoids are keystone drugs in the treatment of childhood acute lymphoblastic leukemia (ALL). To get more insight in signal transduction pathways involved in glucocorticoid-induced apoptosis, Affymetrix U133A GeneChips were used to identify transcriptionally regulated genes on 3 and 8 hours of prednisolone exposure in leukemic cells of 13 children as compared with nonexposed cells. Following 3 hours of exposure no significant changes in gene expression could be identified. Following 8 hours of exposure, 51 genes were differentially expressed (P < .001 and false discovery rate < 10%) with 39 genes being up-regulated (median, 2.4-fold) and 12 genes were down-regulated (median, 1.7-fold). Twenty-one of those genes have not been identified before to be transcriptionally regulated by prednisolone. Two of the 3 most highly up-regulated genes were tumor suppressor genes, that is, thioredoxin-interacting protein (TXNIP; 3.7-fold) and zinc finger and BTB domain containing 16 (ZBTB16; 8.8-fold). About 50% of the differentially expressed genes were functionally categorized in 3 major routes, namely MAPK pathways (9 genes), NF-kappaB signaling (11 genes), and carbohydrate metabolism (5 genes). Biologic characterization of these genes and pathways might elucidate the action of glucocorticoids in ALL cells, possibly suggesting causes of glucocorticoid resistance and new potential targets for therapy.
Insights
Prednisolone treatment in childhood acute lymphoblastic leukemia (ALL) alters gene expression after 8 hours. This study identified 51 differentially expressed genes, including tumor suppressors, offering insights into glucocorticoid action and resistance.
Area of Science:
- Molecular Biology
- Oncology
- Pharmacology
Background:
- Glucocorticoids are crucial for treating childhood acute lymphoblastic leukemia (ALL).
- Understanding glucocorticoid-induced apoptosis pathways is vital for improving ALL treatment.
Purpose of the Study:
- To identify genes and pathways transcriptionally regulated by prednisolone in childhood ALL cells.
- To gain insights into signal transduction mechanisms underlying glucocorticoid-induced apoptosis.
Main Methods:
- Utilized Affymetrix U133A GeneChips to analyze gene expression in leukemic cells from 13 children.
- Compared gene expression after 3 and 8 hours of prednisolone exposure against non-exposed cells.
Main Results:
- No significant gene expression changes were observed after 3 hours.
- After 8 hours, 51 genes were differentially expressed (39 up-regulated, 12 down-regulated).
- Identified novel prednisolone-regulated genes, including tumor suppressors TXNIP and ZBTB16, and highlighted involvement of MAPK, NF-kappaB, and carbohydrate metabolism pathways.
Conclusions:
- Gene expression profiling reveals key pathways affected by prednisolone in ALL cells.
- Findings may elucidate glucocorticoid action, identify causes of resistance, and suggest new therapeutic targets for ALL.
