Glucocorticosteroid Therapy in Childhood Acute Lymphoblastic Leukemia

Gaynon, Paul S.; Carrel, Aaron L.

doi:10.1007/978-1-4615-4811-9_66

Cited by 112 publications

(96 citation statements)

References 59 publications

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“…1,2 In vivo and ex vivo GC sensitivity is furthermore a major prognostic factor in childhood ALL. 3,4 Despite extensive clinical use and research, the molecular mechanisms of GC action remain elusive.…”

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confidence: 99%

Cell death induced by dexamethasone in lymphoid leukemia is mediated through initiation of autophagy

et al. 2009

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Glucocorticoids are fundamental drugs used in the treatment of lymphoid malignancies with apoptotic cell death as the hitherto proposed mechanism of action. Recent studies, however, showed that an alternative mode of cell death, autophagy, is involved in the response to anticancer drugs. The specific role of autophagy and its relationship to apoptosis remains, nevertheless, controversial: it can either lead to cell survival or can function in cell death. We show that dexamethasone induced autophagy upstream of apoptosis in acute lymphoblastic leukemia cells. Inhibition of autophagy by siRNA-mediated repression of Beclin 1 expression inhibited apoptosis showing an important role of autophagy in dexamethasone-induced cell death. Dexamethasone treatment caused an upregulation of promyelocytic leukemia protein, PML, its complex formation with protein kinase B or Akt and a PML-dependent Akt dephosphorylation. Initiation of autophagy and the onset of apoptosis were both dependent on these events. PML knockout thymocytes were resistant to dexamethasone-induced death and upregulation of PML correlated with the ability of dexamethasone to kill primary leukemic cells. Our data reveal key mechanisms of dexamethasone-induced cell death that may inform the development of improved treatment protocols for lymphoid malignancies.

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confidence: 99%

Cell death induced by dexamethasone in lymphoid leukemia is mediated through initiation of autophagy

et al. 2009

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Section: Introductionmentioning

confidence: 99%

“…Glucocorticoids are the most effective and commonly used agents for treatment of B-ALL; however, their efficacy is often hampered by the development of resistance (1). In fact, glucocorticoid sensitivity at diagnosis has a major bearing on the eventual clinical outcome for patients with childhood (B-ALL (1). In consequence, uncovering the mechanisms that underlie dexamethasone responsiveness will not only help identify reliable biomarkers for early diagnosis and for predicting disease relapse but also aid the design of targeted therapies to overcome glucocorticoid resistance in B-ALL.…”

Section: Introductionmentioning

confidence: 99%

“…In consequence, uncovering the mechanisms that underlie dexamethasone responsiveness will not only help identify reliable biomarkers for early diagnosis and for predicting disease relapse but also aid the design of targeted therapies to overcome glucocorticoid resistance in B-ALL. Despite this, the molecular mechanisms underlying glucocorticoid response and resistance remain poorly understood (1).…”

Section: Introductionmentioning

confidence: 99%

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FOXO3a and Posttranslational Modifications Mediate Glucocorticoid Sensitivity in B-ALL

Consolaro

Ghaem‐Maghami

Bortolozzi

et al. 2015

Molecular Cancer Research

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Glucocorticoids are widely used to treat B acute lymphoblastic leukemia (B-ALL); however, the molecular mechanism underlying glucocorticoid response and resistance is unclear. In this study, the role and regulation of FOXO3a in mediating the dexamethasone response in B-ALL were investigated. The results show that FOXO3a mediates the cytotoxic function of dexamethasone. In response to dexamethasone, it was found that FOXO3a translocates into the nucleus, where it induces the expression of downstream targets, including p27Kip1 and Bim, important for proliferative arrest and cell death in the sensitive RS4;11 and SUP-B15 B-ALL cells. FOXO3a activation by dexamethasone is mediated partially through the suppression of the PI3K/Akt signaling cascade. Furthermore, two posttranslational modifications were uncovered, phosphorylation on Ser-7 and acetylation on Lys-242/5, that associated with FOXO3a activation by dexamethasone. Immunoblot analysis showed that the phosphorylation on Ser-7 of FOXO3a is associated with p38/ JNK activation, whereas the acetylation on Lys-242/5 is correlated with the downregulation of SIRT1/2/6 and the induction of the acetyltransferase CBP/p300. Collectively, these results indicate that FOXO3a is essential for dexamethasone response in B-ALL cells, and its nuclear translocation and activation is associated with its phosphorylation on Ser-7 and acetylation on Lys-242/245. These posttranslational events can be exploited as biomarkers for B-ALL diagnosis and as drug targets for B-ALL treatment, particularly for overcoming the glucocorticoid resistance.Implications: FOXO3a and its posttranslational regulation are essential for dexamethasone response, and targeting FOXO3a and sirtuins may enhance the dexamethasone-induced cytotoxicity in B-ALL cells.

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“…Due to their potent lethal effect on lymphoid cells, GC are used as a backbone drug in most treatment protocols for various lymphoid malignancies, including acute lymphoblastic leukemia (ALL). 1,2 Sensitivity to GC-treatment in vivo is also a major prognostic factor in childhood ALL. 3 The in vitro effect of GC on lymphoid cells is dramatic and includes the induction of G0/G1 cell cycle arrest and apoptosis.…”

mentioning

confidence: 99%

Dexamethasone-induced apoptosis in acute lymphoblastic leukemia involves differential regulation of Bcl-2 family members

Laane¹,

Panaretakis²,

Pokrovskaja³

et al. 2007

Haematologica

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Glucocorticosteroid Therapy in Childhood Acute Lymphoblastic Leukemia

Cited by 112 publications

References 59 publications

Cell death induced by dexamethasone in lymphoid leukemia is mediated through initiation of autophagy

Cell death induced by dexamethasone in lymphoid leukemia is mediated through initiation of autophagy

FOXO3a and Posttranslational Modifications Mediate Glucocorticoid Sensitivity in B-ALL

Dexamethasone-induced apoptosis in acute lymphoblastic leukemia involves differential regulation of Bcl-2 family members

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