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.

[Effect of splenic mononuclear cells on autochthonous peripheral blood lymphocyte responses to mitogens in gastric cancer patients].

Mononuclear cells and their fractions which were prepared from spleens removed at the time of surgery for gastric cancer were treated with mitomycin C and their effect on autochthonous peripheral blood lymphocyte responses to PHA-P and Con A was assessed in coculture experiments. Splenic mitomycin C treated mononuclear cells from certain gastric cancer patients were found to have suppressor activity on peripheral blood lymphocyte responses to PHA-P and Con A and the cells with the activity were either plastic dish adherent cells or T-enriched cells alone or both of them. The suppressor activity were more frequently detected in patients with stage IV disease and the patients with the activity tended to exhibit more decreased cell mediated immunocompetence than those without it. Splenic mitomycin C treated mononuclear cells from certain gastric cancer patients were also found to have augmenting activity on peripheral blood lymphocyte responses to PHA-P and the cells with the activity were either plastic dish adherent cells or T-enriched cells or all of plastic dish adherent cells and T- and B-enriched cells.