Divergent Mechanisms of Glucocorticoid Resistance in Experimental Models of Pediatric Acute Lymphoblastic Leukemia

Bachmann, Petra; Gorman, Rosemary; Papa, Rachael A.; Bardell, Jane E.; Ford, Jette; Kees, Ursula R.; Marshall, Glenn M.; Lock, Richard B.

doi:10.1158/0008-5472.can-06-4244

Cited by 107 publications

(119 citation statements)

References 45 publications

Supporting

Mentioning

108

Contrasting

Order By: Relevance

“…PDX cells were prepared for in vitro culture as described previously. 56 Lineage subtype and other details of PDXs and cell lines are shown in Table 1.…”

Section: Patients Materials and Methodsmentioning

confidence: 99%

“…57 In vitro cytotoxicity assays In vitro drug sensitivity was assessed using the colorimetric methyl-thiazolyl-tetrazolium (MTT) assay, and is described elsewhere. 56 The cells were exposed to etoposide (Sigma-Aldrich, #E1383), vorinostat (donation from Merck Research Laboratories), terameprocol (donation from Erimos Pharmaceuticals) or an equivalent volume of dimethyl sulfoxide (DMSO) vehicle (Sigma-Aldrich).…”

Section: In Vitro Cell Culturementioning

confidence: 99%

“…56 Primers and probes for CDKN1A (p21 WAF1 gene) were purchased from Applied Biosystems (Hs00355782_m1). The Elongation factor-1a (EF-1a) gene was an internal standard in each reaction (primers EF-1aF, 5 0 -CTGAACCATCCAGGCCAAAT-3 0 ; EF-1aR, 5 0 -GCCGTG TGGCAATCCAAT-3 0 ; Probe, 5 0 -VIC-AGCGCCGGCTATG CCCCTG-TAMRA-3 0 ).…”

Section: In Vitro Cell Culturementioning

confidence: 99%

“…23,56 697 cell line lysates were prepared using lysis buffer supplied by Cell Signaling Technology (New England Biolabs, #9803), containing a protease inhibitor cocktail (Roche, UK). Membranes were probed with mouse antibodies for p21 WAF1 (clone SX118BD: BD Transduction Laboratories, #556430 or clone 70: BD Biosciences, #610234) and rabbit or mouse antibodies for actin (Sigma-Aldrich #A3853 or Clone JLA20, Calbiochem, #MABT219), followed by horseradish peroxidase (HRP) conjugated donkey anti-rabbit, sheep anti-mouse secondary antibodies (GE Healthcare, #RPN4301 and #RPN4201), or goat anti-mouse or anti-rabbit secondary antibodies (Dako, #P044701-2 and #P044801-2).…”

Section: Analysis Of Protein Expressionmentioning

confidence: 99%

See 3 more Smart Citations

p21^WAF1 modulates drug-induced apoptosis and cell cycle arrest in B-cell precursor acute lymphoblastic leukemia

Davies¹,

Hogarth

MacKenzie³

et al. 2015

Cell Cycle

View full text Add to dashboard Cite

Keywords: childhood acute lymphoblastic leukemia, etoposide, p21 WAF1 , patient derived xenograft models, terameprocol, vorinostat p21 WAF1 is a well-characterized mediator of cell cycle arrest and may also modulate chemotherapy-induced cell death. The role of p21 WAF1 in drug-induced cell cycle arrest and apoptosis of acute lymphoblastic leukemia (ALL) cells was investigated using p53-functional patient-derived xenografts (PDXs), in which p21 WAF1 was epigenetically silenced in T-cell ALL (T-ALL), but not in B-cell precursor (BCP)-ALL PDXs. Upon exposure to diverse cytotoxic drugs, T-ALL PDX cells exhibited markedly increased caspase-3/7 activity and phosphatidylserine (PS) externalization on the plasma membrane compared with BCP-ALL cells. Despite dramatic differences in apoptotic characteristics between T-ALL and BCP-ALL PDXs, both ALL subtypes exhibited similar cell death kinetics and were equally sensitive to p53-inducing drugs in vitro, although T-ALL PDXs were significantly more sensitive to the histone deacetylase inhibitor vorinostat. Transient siRNA suppression of p21 WAF1 in the BCP-ALL 697 cell line resulted in a moderate depletion of the cell fraction in G1 phase and marked increase in PS externalization following exposure to etoposide. Furthermore, stable lentiviral p21 WAF1 silencing in the BCP-ALL Nalm-6 cell line accelerated PS externalization and cell death following exposure to etoposide and vorinostat, supporting previous findings. Finally, the Sp1 inhibitor, terameprocol, inhibited p21 WAF1 expression in Nalm-6 cells exposed to vorinostat and also partially augmented vorinostat-induced cell death. Taken together, these findings demonstrate that p21 WAF1 regulates the early stages of drug-induced apoptosis in ALL cells and significantly modulates their sensitivity to vorinostat.

show abstract

“…PDX cells were prepared for in vitro culture as described previously. 56 Lineage subtype and other details of PDXs and cell lines are shown in Table 1.…”

Section: Patients Materials and Methodsmentioning

confidence: 99%

Section: In Vitro Cell Culturementioning

confidence: 99%

Section: In Vitro Cell Culturementioning

confidence: 99%

Section: Analysis Of Protein Expressionmentioning

confidence: 99%

See 2 more Smart Citations

p21^WAF1 modulates drug-induced apoptosis and cell cycle arrest in B-cell precursor acute lymphoblastic leukemia

Davies¹,

Hogarth

MacKenzie³

et al. 2015

Cell Cycle

View full text Add to dashboard Cite

show abstract

“…Xenografts were previously established from direct patient explants (36) and are representative of BCP-ALL and T-ALL derived from patients with diverse treatment outcomes (see supplemental Table S1). Xenograft cells were retrieved from cryostorage and prepared for in vitro culture as described previously (37).…”

Section: Methodsmentioning

confidence: 99%

p53-independent Epigenetic Repression of the p21WAF1 Gene in T-cell Acute Lymphoblastic Leukemia

Davies

Hogarth

Dietrich

et al. 2011

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

Tamoxifen induces toxicity, causes autophagy, and partially reverses dexamethasone resistance in Jurkat T cells

Torres-López

Maycotte

Liñán-Rico

et al. 2019

Journal of Leukocyte Biology

View full text Add to dashboard Cite

Estrogens demonstrate biological activity in numerous organ systems, including the immune system, and exert their effects through estrogen receptors (ER) of two types: intracellular ERα and ERβ that activate transcriptional factors and membrane G protein‐coupled ER GPER. The latter is capable to mediate fast activation of cytosolic signaling pathways, influencing transcriptional events in response to estrogens. Tamoxifen (TAM), widely used in chemotherapy of ERα‐positive breast cancer, is considered as an ERα antagonist and GPER agonist. TAM was shown to possess “off‐target” cytotoxicity, not related to ER in various tumor types. The present work was designed to study biological effects of TAM on the glucocorticoid (GC)‐resistant cell line Jurkat, derived from acute lymphoblastic leukemia of T lineage (T‐ALL). We have shown that T‐ALL cell lines, in contrast to healthy T cells, express only GPER, but not ERα or ERβ. TAM compromised mitochondrial function and reduced the viability and proliferation of Jurkat cells. Additionally, TAM induced autophagy in a GPER‐dependent manner. Gene expression profiling revealed the up‐regulation of autophagy‐related gene ATG5. Interestingly, TAM sensitized Jurkat cells to dexamethasone (DEX) treatment, which may be related to its capacity to cause autophagy. We suggest that TAM‐based adjuvant therapy may represent a novel strategy in T‐ALL patients handling.

show abstract

Divergent Mechanisms of Glucocorticoid Resistance in Experimental Models of Pediatric Acute Lymphoblastic Leukemia

Cited by 107 publications

References 45 publications

p21^WAF1 modulates drug-induced apoptosis and cell cycle arrest in B-cell precursor acute lymphoblastic leukemia

p21^WAF1 modulates drug-induced apoptosis and cell cycle arrest in B-cell precursor acute lymphoblastic leukemia

p53-independent Epigenetic Repression of the p21WAF1 Gene in T-cell Acute Lymphoblastic Leukemia

Tamoxifen induces toxicity, causes autophagy, and partially reverses dexamethasone resistance in Jurkat T cells

Contact Info

Product

Resources

About

Divergent Mechanisms of Glucocorticoid Resistance in Experimental Models of Pediatric Acute Lymphoblastic Leukemia

Cited by 107 publications

References 45 publications

p21WAF1 modulates drug-induced apoptosis and cell cycle arrest in B-cell precursor acute lymphoblastic leukemia

p21WAF1 modulates drug-induced apoptosis and cell cycle arrest in B-cell precursor acute lymphoblastic leukemia

p53-independent Epigenetic Repression of the p21WAF1 Gene in T-cell Acute Lymphoblastic Leukemia

Tamoxifen induces toxicity, causes autophagy, and partially reverses dexamethasone resistance in Jurkat T cells

Contact Info

Product

Resources

About

p21^WAF1 modulates drug-induced apoptosis and cell cycle arrest in B-cell precursor acute lymphoblastic leukemia

p21^WAF1 modulates drug-induced apoptosis and cell cycle arrest in B-cell precursor acute lymphoblastic leukemia