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

Atul Bedi, J. P. Barber, G. C. Bedi, W. S. El-Deiry, David Sidransky, M. S. Vala, A. J. Akhtar, J. Hilton, Richard J Jones

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1148-1158
Number of pages11
JournalBlood
Volume86
Issue number3
StatePublished - 1995

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Antineoplastic Agents
DNA Damage
Apoptosis
DNA
Genes
G2 Phase Cell Cycle Checkpoints
G1 Phase Cell Cycle Checkpoints
Repair
p53 Genes
Cells
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Cell Cycle Checkpoints
Tumor Suppressor Genes
DNA Replication
DNA Repair
Cell Death
Cell death
Tumors
Chemical activation
Neoplasms

ASJC Scopus subject areas

  • Hematology

Cite this

BCR-ABL-mediated inhibition of apoptosis with delay of G2/M transition after DNA damage : A mechanism of resistance to multiple anticancer agents. / Bedi, Atul; Barber, J. P.; Bedi, G. C.; El-Deiry, W. S.; Sidransky, David; Vala, M. S.; Akhtar, A. J.; Hilton, J.; Jones, Richard J.

In: Blood, Vol. 86, No. 3, 1995, p. 1148-1158.

Research output: Contribution to journalArticle

Bedi, Atul ; Barber, J. P. ; Bedi, G. C. ; El-Deiry, W. S. ; Sidransky, David ; Vala, M. S. ; Akhtar, A. J. ; Hilton, J. ; Jones, Richard J. / BCR-ABL-mediated inhibition of apoptosis with delay of G2/M transition after DNA damage : A mechanism of resistance to multiple anticancer agents. In: Blood. 1995 ; Vol. 86, No. 3. pp. 1148-1158.
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