The BCR/ABL tyrosine kinase induces production of reactive oxygen species in hematopoietic cells

J Biol Chem. 2000 Aug 11;275(32):24273-8. doi: 10.1074/jbc.M002094200.

Abstract

The BCR/ABL oncogene causes chronic myelogenous leukemia, a myeloproliferative disorder characterized by clonal expansion of hematopoietic progenitor cells and myeloid cells. It is shown here that transformation of the hematopoietic cell lines Ba/F3, 32Dcl3, and MO7e with BCR/ABL results in an increase in reactive oxygen species (ROS) compared with quiescent, untransformed cells. The increase in ROS was directly due to BCR/ABL because it was blocked by the ABL-specific tyrosine kinase inhibitor STI571. Oxidative stress through ROS is believed to have many biochemical effects, including the potential ability to inhibit protein-tyrosine phosphatases (PTPases). To understand the significance of increased production of ROS, a model system was established in which hydrogen peroxide (H(2)O(2)) was added to untransformed cells to mimic the increase in ROS induced constitutively by BCR/ABL. H(2)O(2) substantially reduced total cellular PTPase activity to a degree approximately equivalent to that of pervanadate, a well known PTPase inhibitor. Further, stimulation of untransformed cells with H(2)O(2) or pervanadate increased tyrosine phosphorylation of each of the most prominent known substrates of BCR/ABL, including c-ABL, c-CBL, SHC, and SHP-2. Treatment of the BCR/ABL-expressing cell line MO7/p210 with the reducing agents pyrrolidine dithiocarbamate or N-acetylcysteine reduced the accumulation of ROS and also decreased tyrosine phosphorylation of cellular proteins. Further, treatment of MO7e cells with H(2)O(2) or pervanadate increased the tyrosine kinase activity of c-ABL. Drugs that alter ROS metabolism or reactivate PTPases may antagonize BCR/ABL transformation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Line
  • Cell Transformation, Neoplastic
  • Fusion Proteins, bcr-abl / metabolism*
  • Hematopoietic Stem Cells / metabolism*
  • Humans
  • Hydrogen Peroxide / pharmacology
  • Megakaryocytes / metabolism*
  • Mice
  • Protein Tyrosine Phosphatases / metabolism
  • Protein-Tyrosine Kinases / metabolism*
  • Reactive Oxygen Species / metabolism*
  • Rotenone / pharmacology
  • Signal Transduction
  • Vanadates / pharmacology

Substances

  • Reactive Oxygen Species
  • pervanadate
  • Rotenone
  • Vanadates
  • Hydrogen Peroxide
  • Protein-Tyrosine Kinases
  • Fusion Proteins, bcr-abl
  • Protein Tyrosine Phosphatases