Glyoxalase-I is a novel target against Bcr-Abl leukemic cells acquiring stem-like characteristics in a hypoxic environment

M. Takeuchi, S. Kimura, J. Kuroda, E. Ashihara, M. Kawatani, H. Osada, K. Umezawa, E. Yasui, M. Imoto, T. Tsuruo, A. Yokota, R. Tanaka, R. Nagao, T. Nakahata, Y. Fujiyama, T. Maekawa

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Abstract

Abl tyrosine kinase inhibitors (TKIs) such as imatinib and dasatinib are ineffective against Bcr-Abl leukemic stem cells. Thus, the identification of novel agents that are effective in eradicating quiescent Bcr-Abl stem cells is needed to cure leukemias caused by Bcr-Abl cells. Human Bcr-Abl cells engrafted in the bone marrow of immunodeficient mice survive under severe hypoxia. We generated two hypoxia-adapted (HA)-Bcr-Abl sublines by selection in long-term hypoxic cultures (1.0% O 2). Interestingly, HA-Bcr-Abl cells exhibited stem cell-like characteristics, including more cells in a dormant, increase of side population fraction, higher Β-catenin expression, resistance to Abl TKIs, and a higher transplantation efficiency. Compared with the respective parental cells, HA-Bcr-Abl cells had higher levels of protein and higher enzyme activity of glyoxalase-I (Glo-I), an enzyme that detoxifies methylglyoxal, a cytotoxic by-product of glycolysis. In contrast to Abl TKIs, Glo-I inhibitors were much more effective in killing HA-Bcr-Abl cells both in vitro and in vivo. These findings indicate that Glo-I is a novel molecular target for treatment of Bcr-Abl leukemias, and, in particular, Abl TKI-resistant quiescent Bcr-Abl leukemic cells that have acquired stem-like characteristics in the process of adapting to a hypoxic environment.

Original languageEnglish
Pages (from-to)1211-1220
Number of pages10
JournalCell Death and Differentiation
Volume17
Issue number7
DOIs
Publication statusPublished - 2010 Jul 1

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Keywords

  • Abl tyrosine kinase
  • Glo-I
  • Hypoxia
  • Leukemia
  • Stem cell

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Takeuchi, M., Kimura, S., Kuroda, J., Ashihara, E., Kawatani, M., Osada, H., Umezawa, K., Yasui, E., Imoto, M., Tsuruo, T., Yokota, A., Tanaka, R., Nagao, R., Nakahata, T., Fujiyama, Y., & Maekawa, T. (2010). Glyoxalase-I is a novel target against Bcr-Abl leukemic cells acquiring stem-like characteristics in a hypoxic environment. Cell Death and Differentiation, 17(7), 1211-1220. https://doi.org/10.1038/cdd.2010.6