Glucocorticoid-Induced Apoptosis and Treatment Sensitivity in Acute Lymphoblastic Leukemia of Children

Csóka, Monika; Bocsi, József; Falus, András; Szalai, Cs.; Klujber, V.; Szende, B.; Schüler, D.

doi:10.3109/08880019709028773

Cited by 12 publications

(8 citation statements)

References 11 publications

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“…In clinical studies, GR expression levels above B10 000 copies per cell at diagnosis correlated with beneficial outcome in childhood ALL, 103,104 but this correlation is not a consistent finding. 105,106 As discussed previously, GR levels at the onset of treatment may not be as important as GR expression kinetics (up-or downregulation) during treatment, but clinical studies addressing this question have not been reported thus far.…”

Section: 'Upstream Mechanisms-2': Gr Mutations Splice Variants or Inmentioning

confidence: 99%

Glucocorticoid-induced apoptosis and glucocorticoid resistance: molecular mechanisms and clinical relevance

et al. 2004

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The ability of glucocorticoids (GC) to efficiently kill lymphoid cells has led to their inclusion in essentially all chemotherapy protocols for lymphoid malignancies. This review summarizes recent findings related to the molecular basis of GC-induced apoptosis and GC resistance, and discusses their potential clinical implications. Accumulating evidence suggests that GC may induce cell death via different pathways resulting in apoptotic or necrotic morphologies, depending on the availability/responsiveness of the apoptotic machinery. The former might result from regulation of typical apoptosis genes such as members of the Bcl-2 family, the latter from detrimental GC effects on essential cellular functions possibly perpetuated by GC receptor (GR) autoinduction. Although other possibilities exist, GC resistance might frequently result from defective GR expression, perhaps the most efficient means to target multiple antileukemic GC effects. Numerous novel drug combinations are currently being tested to prevent resistance and improve GC efficacy in the therapy of lymphoid malignancies.

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Section: 'Upstream Mechanisms-2': Gr Mutations Splice Variants or Inmentioning

confidence: 99%

Glucocorticoid-induced apoptosis and glucocorticoid resistance: molecular mechanisms and clinical relevance

et al. 2004

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“…Steroid hormones are among the key systemic factors that are directly involved in the proliferative control of normal and neoplastically transformed cells. Although tumor cells often proliferate uncontrollably under conditions where nontransformed cells would be quiescent (1)(2)(3), treatment with certain steroid agonists and antagonists can induce a cell cycle arrest or apoptotic response in many tumor cell types (4)(5)(6)(7)(8)(9)(10). Glucocorticoids, one class of steroid hormones, are potent anti-proliferative agents affecting a variety of cell and tissue types, with liver and mammary-derived epithelial cells being particularly sensitive to the growth inhibitory effects of this steroid (11)(12)(13)(14)(15)(16).…”

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confidence: 99%

Dysfunctional glucocorticoid receptor with a single point mutation ablates the CCAAT/enhancer binding protein‐dependent growth suppression response in a steroid‐resistant rat hepatoma cell variant

et al. 1999

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We used glucocorticoid-resistant and -sensitive hepatoma cell variants to characterize the mechanism of hepatoma cell resistance to the growth inhibitory effects of glucocorticoids. BDS1 hepatoma cells express transcriptionally active glucocorticoid receptors and undergo a stringent G1 cell cycle arrest in response to glucocorticoids that is dependent on the induced expression of the CCAAT/enhancer binding protein alpha (C/EBPalpha) transcription factor. In contrast, EDR1 hepatoma cells, which express normal levels of glucocorticoid receptors, fail to growth arrest or express C/EBPalpha when treated with glucocorticoids. Ectopic expression of wild-type rat glucocorticoid receptors into EDR1 cells restored the growth suppression response, suggesting a defect in the EDR1 receptor. DNA sequence analysis revealed a single point mutation causing a cysteine-to-tyrosine substitution at amino acid position 457 (C457Y-GR) in the zinc finger region of the glucocorticoid receptor that mediates both receptor-DNA and receptor-protein interactions. Glucocorticoid activation of the alpha1-acid glycoprotein (AGP) promoter, a liver acute-phase response gene, requires receptor-DNA binding as well as an interaction with C/EBPalpha. In contrast to the wild-type glucocorticoid receptor, ectopic expression of C/EBPalpha in EDR1 cells, or coexpression of C/EBPalpha along with the C457Y-GR into receptor-deficient EDR3 cells was required to partially restore glucocorticoid responsiveness of the AGP promoter by the EDR1 glucocorticoid receptor. Constitutive expression of the wild-type glucocorticoid receptor, but not the C457Y-GR mutant, was sufficient to restore the glucocorticoid growth suppression response to receptor-deficient EDR3 cells. Thus, we have identified a glucocorticoid-resistant hepatoma cell variant with a single point mutation in the zinc finger region of the glucocorticoid receptor gene that ablates the glucocorticoid growth suppression response and attenuates transcriptional activation of the AGP promoter.

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“…Glucocorticoids (GCs) were one of the earliest recognized drug groups for the treatment of leukemias and lymphomas [Csoka et al, 1997;reviewed in Stevens and Stevens, 1985] and are still widely in use. In lymphoproliferative diseases, the mechanism by which the hormones impart their therapeutic effect is not well understood.…”

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confidence: 99%

Association of the glucocorticoid receptor alternatively-spliced transcript 1A with the presence of the high molecular weight membrane glucocorticoid receptor in mouse lymphoma cells

1999

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Using the combination of a cDNA library prepared from membrane glucocorticoid (mGR)-enriched S-49 cells and a mouse leukocyte genomic library, we have cloned a 7.3 kb full-length glucocorticoid receptor 1A cDNA. Primer extension, 5'RACE, and long distance PCR identified the transcription start site as being located at 1026 bp from the ATG codon. The first 1,013 nucleotides (nts) of the full length sequence constitute 5' UTR sequence (exon 1), the next 2349 bp, the coding region, and the last 3,907 bp, the 3'UTR. The entire 5'UTR sequence is unique to transcript 1A. The 3'UTR sequence is approximately 88.5 % conserved with the rat 3'UTR. Western blot analysis compared the molecular weight of in vitro translation products from the cloned 1A cDNA with partially purified cellular mGR. Both preparations contained the novel 150 KD and the 94 KD classical GR peptides, suggesting that transcript 1A encodes both receptor forms. Transfection of mGR-less and glucocorticoid lysis-resistant AtT-20 and HL-60 cells with full-length GR 1A cDNA imparted both mGR expression and glucocorticoid lysis-sensitivity to these cells.

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Glucocorticoid-Induced Apoptosis and Treatment Sensitivity in Acute Lymphoblastic Leukemia of Children

Cited by 12 publications

References 11 publications

Glucocorticoid-induced apoptosis and glucocorticoid resistance: molecular mechanisms and clinical relevance

Glucocorticoid-induced apoptosis and glucocorticoid resistance: molecular mechanisms and clinical relevance

Dysfunctional glucocorticoid receptor with a single point mutation ablates the CCAAT/enhancer binding protein‐dependent growth suppression response in a steroid‐resistant rat hepatoma cell variant

Association of the glucocorticoid receptor alternatively-spliced transcript 1A with the presence of the high molecular weight membrane glucocorticoid receptor in mouse lymphoma cells

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