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

研究成果: Article査読

34 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)1211-1220
ページ数10
ジャーナルCell Death and Differentiation
17
7
DOI
出版ステータスPublished - 2010 7

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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