Gene expression profile of human lymphoid CEM cells sensitive and resistant to glucocorticoid-evoked apoptosis

Abstract

Three closely related clones of leukemic lymphoid CEM cells were compared for their gene expression responses to the glucocorticoid dexamethasone (Dex). All three contained receptors for Dex, but only two responded by undergoing apoptosis. After a time of exposure to Dex that ended late in the interval preceding onset of apoptosis, gene microarray analyses were carried out. The results indicate that the expression of a limited, distinctive set of genes was altered in the two apoptosis-prone clones, not in the resistant clone. That clone showed altered expression of different sets of genes, suggesting that a molecular switch converted patterns of gene expression between the two phenotypes: apoptosis-prone and apoptosis-resistant. The results are consistent with the hypothesis that altered expression of a distinctive network of genes after glucocorticoid administration ultimately triggers apoptosis of leukemic lymphoid cells. The altered genes identified provide new foci for study of their role in cell death.

Calcium-dependent upregulation of E4BP4 expression correlates with glucocorticoid-evoked apoptosis of human leukemic CEM cells

“…As described in the literature [7], and shown in Figure 1 s of Supplementary Materials, the CEM sister clones CEM-C7-14 and CEM-C1-15 are sensitive and resistant, respectively, to GCevoked apoptotic cell death.…”

“…Among the list of genes upregulated in only those CEM cell clones that are susceptible to GCevoked apoptosis, but not in a CEM clone non-responsive to GCs, is the gene for adenoviral E4 binding protein 4 (E4BP4) [7], an evolutionarily conserved transcriptional repressor belonging to the bZIP family of transcription factors [9]. GR-evoked transcriptional repression has been shown to be important for GC-evoked apoptosis [30].…”

“…Microarray analysis of GC-sensitive and -resistant human leukemic lymphoblastoid CEM cells has identified E4BP4 as a gene that is upregulated in response to GCs only in cells susceptible to GC-evoked apoptosis [7]. E4BP4 is a member of the basic region/leucine zipper (bZIP) containing family of transcription factors and shares DNA binding specificities with factors such as c-Jun and CREB [8].…”

Authenticity and drug resistance in a panel of acute lymphoblastic leukaemia cell lines

“…A similar drug profile was observed in the B-lineage cell lines (Figure 1, shaded boxes). The parental CCRF-CEM cell line is known to represent a mixed population of sensitive and resistant clones (Medh et al, 2003); IC 50 values for DEX and ASP for this cell line (Table 2) were much higher than have been reported elsewhere (Martin-Aragon et al, 2000;Catts et al, 2001;van der Heijden et al, 2004), indicating that our CEM represents a resistant sub-clone that has grown out during culture.…”

Apoptosis inhibition by Bcl-2 gives way to autophagy in glucocorticoid-treated lymphocytes

“…2,3 In addition to apoptosis-related genes, gene expression profiling has uncovered glucocorticoid regulation of genes involved in cellular metabolism, including genes that regulate glucose homeostasis and respond to ER stress. 2,[4][5][6][7] This is not surprising since it has been known for over forty years that glucocorticoids inhibit glucose uptake and glycolysis in thymocytes. 8,9 These welldocumented effects on lymphocyte metabolism suggested to us that glucocorticoids might induce macroautophagy (hereafter referred to as autophagy), as well as apoptosis.…”