Genome-Wide Identification of Prednisolone-Responsive Genes in Primary Acute Lymphoblastic Leukemia Cells.

Glucocorticoids (GC) are keystone drugs in the treatment of childhood ALL and therefore it is important to get more insight in signal transduction pathways involved in GC induced apoptosis. Affymetrix U133A GeneChips were used to identify genes that are transcriptionally regulated upon 3 and 8 hours of prednisolone exposure in leukemic cells of 13 children newly diagnosed with ALL. After 3 hours of exposure no changes in gene expression could yet be found. After 8 hours exposure, 57 probesets (51 unique genes) were differentially expressed (p<0.0005 and false discovery rate <0.1) of which 44 probesets (39 genes) were upregulated (median 2.4-fold), whereas 13 probesets (12 genes) were downregulated (median 1.7-fold). Twenty-one genes were not previously found to be transcriptionally regulated by GC. Two tumor suppressor genes, Thioredoxin interacting protein (TXNIP) and Zinc finger and BTB domain containing 16 (ZBTB16), were 3.7-fold and 8.8-fold upregulated. Genes were functionally categorized in three major routes: i.e. MAPK pathways (9 genes), NF-k B signaling (11 genes) and carbohydrate metabolism (6 genes).

Biological characterization of these genes and pathways might elucidate the action of GC in leukemic cells. This knowledge may point to causes of GC resistance, ways to circumvent GC resistance and new potential targets for therapy.