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- Title
Glyoxalase-I is a novel target against Bcr-Abl<sup>+</sup> leukemic cells acquiring stem-like characteristics in a hypoxic environment.
- Authors
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.
- 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% O2). 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.
- Publication
Cell Death & Differentiation, 2010, Vol 17, Issue 7, p1211
- ISSN
1350-9047
- Publication type
Academic Journal
- DOI
10.1038/cdd.2010.6