p21WAF1 modulates drug-induced apoptosis and cell cycle arrest in B-cell precursor acute lymphoblastic leukemia |
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Authors: | Carwyn Davies Linda A Hogarth Karen L Mackenzie Andrew G Hall Richard B Lock |
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Affiliation: | 1.Children''s Cancer Institute; Lowy Cancer Research Centre; UNSW Australia; Sydney, NSW, Australia;2.Northern Institute for Cancer Research; Newcastle University; Newcastle upon Tyne; Tyne and Wear, UK;3.Clinical Pharmacology Modeling and Simulation; GlaxoSmithKline R&D; Sydney, Australia |
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Abstract: | p21WAF1 is a well-characterized mediator of cell cycle arrest and may also modulate chemotherapy-induced cell death. The role of p21WAF1 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 p21WAF1 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 p21WAF1 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 p21WAF1 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 p21WAF1 expression in Nalm-6 cells exposed to vorinostat and also partially augmented vorinostat-induced cell death. Taken together, these findings demonstrate that p21WAF1 regulates the early stages of drug-induced apoptosis in ALL cells and significantly modulates their sensitivity to vorinostat. |
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Keywords: | childhood acute lymphoblastic leukemia etoposide p21WAF1 patient derived xenograft models terameprocol vorinostat |
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