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 language | English |
|---|---|
| Pages (from-to) | 1211-1220 |
| Number of pages | 10 |
| Journal | Cell Death and Differentiation |
| Volume | 17 |
| Issue number | 7 |
| DOIs | |
| Publication status | Published - 2010 Jul |
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Keywords
- Abl tyrosine kinase
- Glo-I
- Hypoxia
- Leukemia
- Stem cell
ASJC Scopus subject areas
- Cell Biology
- Molecular Biology
- Medicine(all)
Cite this
Glyoxalase-I is a novel target against Bcr-Abl leukemic cells acquiring stem-like characteristics in a hypoxic environment. / Takeuchi, M.; Kimura, S.; Kuroda, J.; Ashihara, E.; Kawatani, M.; Osada, H.; Umezawa, K.; Yasui, E.; Imoto, Masaya; Tsuruo, T.; Yokota, A.; Tanaka, R.; Nagao, R.; Nakahata, T.; Fujiyama, Y.; Maekawa, T.
In: Cell Death and Differentiation, Vol. 17, No. 7, 07.2010, p. 1211-1220.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Glyoxalase-I is a novel target against Bcr-Abl leukemic cells acquiring stem-like characteristics in a hypoxic environment
AU - Takeuchi, M.
AU - Kimura, S.
AU - Kuroda, J.
AU - Ashihara, E.
AU - Kawatani, M.
AU - Osada, H.
AU - Umezawa, K.
AU - Yasui, E.
AU - Imoto, Masaya
AU - Tsuruo, T.
AU - Yokota, A.
AU - Tanaka, R.
AU - Nagao, R.
AU - Nakahata, T.
AU - Fujiyama, Y.
AU - Maekawa, T.
PY - 2010/7
Y1 - 2010/7
N2 - 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.
AB - 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.
KW - Abl tyrosine kinase
KW - Glo-I
KW - Hypoxia
KW - Leukemia
KW - Stem cell
UR - http://www.scopus.com/inward/record.url?scp=77953619656&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77953619656&partnerID=8YFLogxK
U2 - 10.1038/cdd.2010.6
DO - 10.1038/cdd.2010.6
M3 - Article
VL - 17
SP - 1211
EP - 1220
JO - Cell Death and Differentiation
JF - Cell Death and Differentiation
SN - 1350-9047
IS - 7
ER -