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

Abstract

The p53 protein is a primary mediator of cellular apoptosis and growth arrest after exposure to DNA-damaging agents. Previous work has shown that the majority of childhood acute lymphoblastic leukemia (ALL) cases express a wild type p53 gene, although the functionality of the p53 pathway has rarely been validated. In the present study, the integrity of the p53 pathway

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

“…Yet the influence 23 In the experiments described here, greater caspase-3/7 activity was exhibited by p21 WAF1 -defective T-ALL PDXs after exposure to etoposide and vorinostat in comparison to p21 WAF1 -functional BCP-ALL cells. Maximal caspase activity also occurred earlier in T-ALL cells than in BCP-ALL PDXs, demonstrating increased apoptotic kinetics in T-ALL samples.…”

“…The p53 status and p21 WAF1 responses of the PDXs used in this study have previously been determined and are summarized in Table 1. 23 To evaluate the apoptotic response of lymphoid leukemia cells to cytotoxic agents that induce p21 WAF1 , we assessed caspase-3/7 activity and PS externalization in PDX cells and ALL cell lines exposed to 5 mM of etoposide or vorinostat, with or without prior incubation with the pan-caspase inhibitor z-VAD-FMK for up to 48 h of drug exposure. Caspase-3/7 activity of 2 T-ALL PDXs increased to 2-5 OD450 units/mg protein from <0.6 OD450 units/mg protein within 6 h of exposure to etoposide (Fig.…”

“…In comparison, the p21 WAF1 -defective T-ALL and p21 WAF1 -functional BCP-ALL PDXs demonstrated generally similar sensitivities to the p53-inducing agents, etoposide and nutlin-3. As both T-ALL and BCP-ALL PDXs demonstrated wild-type p53 activity, 23 it would be understandable that both lineages would be equally sensitive to DNA damage and Mdm-2 inhibition. While other perturbations in the p53 pathway besides TP53 gene mutations do exist, this observation suggests that their impact on the in vitro sensitivity of PDX ALL cells would be minimal.…”

“…48 The study herein is the first to report on the anti-apoptotic role of p21 WAF1 in a BCP-lineage leukemia cell line that was previously shown to have an intact p53 response to DNA damaging agents. 23 Reports of p21 WAF1 attenuating apoptosis in myelomonocytic and promyelocytic leukemia cells have demonstrated that inactivation of p21 WAF1 renders an immediate effect on apoptotic characteristics and drug sensitivity. For example, in the U-937 promyelocytic cell line, increased apoptosis was observed within 4 h of drug exposure.…”

“…16 TP53 mutations represent another mechanism that leads to drug resistance and perturbed initiation of apoptosis in cancer cells, 17 although in diseases such as childhood acute lymphoblastic leukemia (ALL), 18,19 apoptosis can also be inhibited by alternative mechanisms, including ATM inactivation, 20 overexpression of Hdm-2, 21 expression of anti-apoptotic proteins, 22 or dysfunction in the p53-p21 WAF1 axis. 23,24 Upregulation of p21 WAF1 and disruption of the cytotoxic response can occur irrespective of TP53 gene mutations. 20,24,25 In addition, the induction of p21 WAF1 that occurs after exposure to various cytotoxic stimuli can inhibit the apoptosis process in malignant hematopoietic cells [26][27][28] and solid tumor cells.…”