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

Lookup NU author(s): Dr Linda Hogarth, Dr Andrew Hall


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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.

Publication metadata

Author(s): Davies C, Hogarth LA, Mackenzie KL, Hall AG, Lock RB

Publication type: Article

Publication status: Published

Journal: Cell Cycle

Year: 2015

Volume: 14

Issue: 22

Pages: 3602-3612

Acceptance date: 22/09/2015

ISSN (print): 1538-4101

ISSN (electronic): 1551-4005

Publisher: Taylor & Francis Inc.


DOI: 10.1080/15384101.2015.1100774


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Funder referenceFunder name
Australian Postgraduate Award
Children's Cancer Institute Australia for Medical Research
1059804Australian National Health and Medical Research Council
568703Australian National Health and Medical Research Council
6895JGW Pattern Foundation (Newcastle upon Tyne)