BCR-ABL-mediated inhibition of apoptosis with delay of G2/M transition after DNA damage: a mechanism of resistance to multiple anticancer agents

Abstract

A critical determinant of the efficacy of antineoplastic therapy is the response of malignant cells to DNA damage induced by anticancer agents. The p53 tumor-suppressor gene is a critical component of two distinct cellular responses to DNA damage, the induction of a reversible arrest at the G1/S cell cycle checkpoint, and the activation of apoptosis, a genetic program of autonomous cell death. Expression of the BCR-ABL chimeric gene produced by a balanced translocation in chronic myeloid leukemia, confers resistance to multiple genotoxic anticancer agents. BCR-ABL expression inhibits the apoptotic response to DNA damage without altering either the p53-dependent WAF1/CIP1-mediated G1 arrest or DNA repair. BCR-ABL-mediated inhibition of DNA damage-induced apoptosis is associated with a prolongation of cell cycle arrest at the G2/M restriction point; the delay of G2/M transition may allow time to repair and complete DNA replication and chromosomal segregation, thereby preventing a mitotic catastrophe. The inherent resistance of human cancers to genotoxic agents may result not only by the loss or inactivation of the wild-type p53 gene, but also by genetic alterations such as BCR-ABL that can delay G2/M transition after DNA damage.

Molecular alterations in theTP53 gene of peripheral blood cells of patients with chronic myeloid leukemia

“…Since all patients were under treatment, it is possible that this overexpression of TP53 may be a result of chemotherapyinduced DNA damage and inhibition of apoptosis in the cells downstream of TP53 induction. A recent study (Bedi et al, 1995) reported normal induction of TP53 and BCR-ABL mediated inhibition of apoptosis at the G 2 /M transition. We believe that TP53 accumulation may also affect this G 2 /M inhibition.…”

Expression of cyclin A, B1 and D1 after induction of cell cycle arrest in the Jurkat cell line exposed to doxorubicin

“…Like to our results, they found only a limited amount of apoptosis. Inhibited apoptosis accompanied by G2/M delay after DNA damage is a possible mechanism of resistance to anticancer treatment (Bedi et al, 1995). G2/M delay may reflect time needed for DNA replication, chromosomal segregation and repair, in this way preventing cell death.…”

Consequences of BCR‐ABL Expression within the Hematopoietic Stem Cell in Chronic Myeloid Leukemia

“…Signals implicated in the antiapoptotic function of BCR-ABL include PI 3′ kinase/Akt [60,90], STAT5-dependent BCLXL upregulation [91] and NF-κB [92]. In addition, prolonged activation of the G 2 -specific cell cycle checkpoint via maintenance of inhibitory phosphorylation of CDC2 at tyrosine 15 has been ascribed directly to BCR-ABL, and shown to underlie its ability to suppress apoptosis and promote the long-term survival of hematopoietic cells following DNA damage [93,94].…”