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• W1990310347 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." @default.
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• W1990310347 date "2010-02-05" @default.
• W1990310347 modified "2023-10-16" @default.
• W1990310347 title "Glyoxalase-I is a novel target against Bcr-Abl+ leukemic cells acquiring stem-like characteristics in a hypoxic environment" @default.
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• W1990310347 doi "https://doi.org/10.1038/cdd.2010.6" @default.
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