Glyoxalase-I is a novel target against Bcr-Abl+ leukemic cells acquiring stem-like characteristics in a hypoxic environment.
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 beta-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.
Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Kyoto, Japan.
M
M
Takeuchi
S
S
Kimura
J
J
Kuroda
E
E
Ashihara
M
M
Kawatani
H
H
Osada
K
K
Umezawa
E
E
Yasui
M
M
Imoto
T
T
Tsuruo
A
A
Yokota
R
R
Tanaka
R
R
Nagao
T
T
Nakahata
Y
Y
Fujiyama
T
T
Maekawa
D000818:Animals; D001549:Benzamides; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D000069439:Dasatinib; D006801:Humans; D000068877:Imatinib Mesylate; D007791:Lactoylglutathione Lyase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000201:enzymology; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D014183:Transplantation, Heterologous; D051176:beta Catenin / Q000378:metabolism
D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D051176:beta Catenin; D000068877:Imatinib Mesylate; D007791:Lactoylglutathione Lyase; D000069439:Dasatinib