Glucocorticoid Induced Apoptosis in Leukemia

Smets, L. A.; Salomons, Gajja S.; Berg, Joop van den

doi:10.1007/978-1-4615-4811-9_67

Cited by 40 publications

(17 citation statements)

References 25 publications

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“…51 Therefore, we speculate that potential low levels of TOP2A could reduce the pro-apoptotic potential of leukemia cells and hence reduce the sensitivity of these cells to glucocorticoids, which are known to induce apoptosis. 52 As a consequence, blast cells would persist in peripheral blood, leading the children to be classified in the VHR group. In order to confirm this hypothesis, additional investigations at the protein level are now required, first to verify that TOP2A protein levels actually correlate with TOP2A gene status and RNA expression levels.…”

Section: Discussionmentioning

confidence: 99%

Modification of topoisomerase genes copy number in newly diagnosed childhood acute lymphoblastic leukemia

et al. 2003

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Topoisomerase genes were analyzed at both DNA and RNA levels in 25 cases of newly diagnosed childhood acute lymphoblastic leukemia (ALL). The results of molecular analysis were compared to risk group classification of children in order to identify molecular characteristics associated with response to therapy. At diagnosis, allelic imbalance at topoisomerase IIa (TOP2A) gene locus was found in 75% of informative cases whereas topoisomerase I and IIb gene loci are altered in none or only one case, respectively. By semiquantitative Polymerase chain reaction, we found a 2.5 to 8-fold TOP2A gene amplification in 72% of the children, which was correlated to gene overexpression in every case. These results show that TOP2A gene amplification is a frequent event in ALL at diagnosis. Interestingly, we also identified a small population of children that do not present TOP2A gene amplification or gene overexpression and who are significantly associated with very high risk classified patients showing glucocorticoid resistance. In conclusion, characterization of TOP2A gene status in childhood ALL at diagnosis provides useful complementary information for risk assessment.

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Section: Discussionmentioning

confidence: 99%

Modification of topoisomerase genes copy number in newly diagnosed childhood acute lymphoblastic leukemia

et al. 2003

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“…Today glucocorticoids are common components in many chemotherapeutic protocols for lymphoid malignancies, including multiple myeloma, acute lymphoblastic leukemia, chronic lymphocytic leukemia, and non-Hodgkin's lymphoma (3)(4)(5)(6). In fact, glucocorticoid therapy is essential for the successful treatment of childhood acute lymphoblastic leukemia (5).…”

mentioning

confidence: 99%

Microarray Analysis Uncovers the Induction of the Proapoptotic BH3-only Protein Bim in Multiple Models of Glucocorticoid-induced Apoptosis

Wang¹,

Malone²,

He³

et al. 2003

Journal of Biological Chemistry

199

223

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Despite being one of the earliest recognized and most clinically relevant forms of apoptosis, little is known about the transcriptional events that mediate glucocorticoid-induced apoptosis. Therefore, we used oligonucleotide microarrays to identify the pattern of dexamethasone-induced changes in gene expression in two well characterized models of glucocorticoid-induced apoptosis, the murine lymphoma cell lines S49.A2 and WEHI7.2. Dexamethasone treatment induced a diverse set of gene changes that evolved over a 24-h period preceding the onset of cell death. These include previously reported changes in the expression of genes regulating prosurvival signals mediated by c-Myc and NFB. Unexpectedly, we discovered that glucocorticoid treatment increases expression of the gene encoding Bim, a BH3-only member of the Bcl-2 family that is capable of directly activating the apoptotic cascade. Induction of Bim was confirmed by immunoblotting not only in S49.A2 and WEHI7.2 cells but also in the human leukemia cell line CEM-C7 and in primary murine thymocytes. All three prototypical isoforms of Bim (Bim EL , Bim L , and Bim S ) were induced by dexamethasone. Because elevated expression of Bim initiates the execution phase of cell death, this report that Bim is induced by dexamethasone provides novel insight into the mechanism through which glucocorticoid-mediated changes in gene expression induce apoptosis in lymphoid cells.

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“…GCs are effective antileukemic agents and kill T-lymphoid cells by inducing classical apoptosis [1]. GCs modulate their actions via binding to specific cytoplasmic GC receptors (GR), which translocate to the nucleus and regulate transcription of target genes [2].…”

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confidence: 99%

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

Priceman

Kirzner

Nary

et al. 2006

Biochemical and Biophysical Research Communications

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Glucocorticoid (GC)-evoked apoptosis of T-lymphoid cells is preceded by increases in the intracellular Ca 2+ concentration ([Ca 2+ ] i ), which may contribute to apoptosis. This report demonstrates that GC-mediated upregulation of the bZIP transcriptional repressor gene, E4BP4, is dependent on [Ca 2+ ] i levels, and correlates with GC-evoked apoptosis of GC-sensitive CEM-C7-14 cells. Calcium chelators EGTA and BAPTA reduced [Ca 2+ ] i levels and protected CEM-C7-14 cells from Dex-evoked E4BP4 upregulation as well as apoptosis. In the GC-resistant sister clone, CEM-C1-15, Dex treatment did not induce [Ca 2+ ] i levels, E4BP4 expression or apoptosis, however, the calcium ionophore A23187 restored Dex-evoked E4BP4 upregulation and apoptosis. CEM-C7-14 cells were more sensitive to GC-independent increases in [Ca 2+ ] i levels by thapsigargin, and a corresponding increase in E4BP4 expression and cell death, compared to CEM-C1-15 cells, suggesting a direct correlation between [Ca 2+ ] i levels, E4BP4 expression, and apoptosis.

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Glucocorticoid Induced Apoptosis in Leukemia

Cited by 40 publications

References 25 publications

Modification of topoisomerase genes copy number in newly diagnosed childhood acute lymphoblastic leukemia

Modification of topoisomerase genes copy number in newly diagnosed childhood acute lymphoblastic leukemia

Microarray Analysis Uncovers the Induction of the Proapoptotic BH3-only Protein Bim in Multiple Models of Glucocorticoid-induced Apoptosis

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

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