ATR-Chk1 axis protects BCR/ABL leukemia cells from the lethal effect of DNA double-strand breaks

Cell Cycle. 2006 May;5(9):994-1000. doi: 10.4161/cc.5.9.2722. Epub 2006 May 1.

Abstract

BCR/ABL-positive leukemia cells accumulated more replication-dependent DNA double-strand breaks (DSBs) than normal counterparts after treatment with cisplatin and mitomycin C (MMC, as assessed by pulse field gel electrophoresis (PFGE) and neutral comet assay. In addition, leukemia cells could repair these lesions more efficiently than normal cells and eventually survive genotoxic treatment. Elevated levels of drug-induced DSBs in leukemia cells were associated with higher activity of ATR kinase, and enhanced phosphorylation of histone H2AX on serine 139 (gamma-H2AX). gamma-H2AX eventually started to disappear in BCR/ABL cells, while continued to increase in parental cells. In addition, the expression and ATR-mediated phosphorylation of Chk1 kinase on serine 345 were often more abundant in BCR/ABL-positive leukemia cells than normal counterparts after genotoxic treatment. Inhibition of ATR kinase by caffeine but not Chk1 kinase by indolocarbazole inhibitor, SB218078 sensitized BCR/ABL leukemia cells to MMC in a short-term survival assay. Nevertheless, both caffeine and SB218078 enhanced the genotoxic effect of MMC in a long-term clonogenic assay. This effect was associated with the abrogation of transient accumulation of leukemia cells in S and G2/M cell cycle phases after drug treatment. In conclusion, ATR-Chk1 axis was strongly activated in BCR/ABL-positive cells and contributed to the resistance to DNA cross-linking agents causing numerous replication-dependent DSBs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle Proteins / physiology*
  • Checkpoint Kinase 1
  • Cisplatin / pharmacology
  • DNA Damage*
  • Drug Resistance, Neoplasm
  • Enzyme Activation
  • Fusion Proteins, bcr-abl / analysis*
  • Fusion Proteins, bcr-abl / physiology
  • G2 Phase
  • Genomic Instability
  • Humans
  • Kinetics
  • Leukemia / enzymology*
  • Leukemia / pathology
  • Methylnitronitrosoguanidine / pharmacology
  • Mitomycin / pharmacology
  • Protein Kinases / physiology*
  • Protein-Serine-Threonine Kinases / physiology*
  • Reactive Oxygen Species / metabolism
  • S Phase
  • Signal Transduction

Substances

  • Antineoplastic Agents
  • Cell Cycle Proteins
  • Reactive Oxygen Species
  • Methylnitronitrosoguanidine
  • Mitomycin
  • Protein Kinases
  • Fusion Proteins, bcr-abl
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • CHEK1 protein, human
  • Checkpoint Kinase 1
  • Protein-Serine-Threonine Kinases
  • Cisplatin