Eradication of chronic myelogenous leukemia stem cells and abnormal clone with T315I point mutation

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Imatinib mesylate(IM, GleevecR), which specifically inhibits the autophosphorylation of the Abl tyrosine kinase(TK), has dramatically improved the treatment of chronic myelogenous leukemia(CML). However, resistance is often reported in patients with advanced-stage disease. Several novel TK inhibitors(TKI) of second generation such as dasatinib(SprycelR), nilotinib(TasignaR), and INNO-406(Bafetinib) have been developed that override IM resistance mechanisms caused by point mutations within the Abl kinase domain. Because of their strong affinities for the ATP-binding site compared to IM, these new TKIs may be effective in IM-resistant patients. However, they could not inhibit the phosphorylation of T315I Bcr-Abl harboring the mutation of threonine 315 to isoleucine. We describe the in vitro and in vivo effects of AT9283(1-cyclopropyl-3[5-morpholin-4yl methyl-1H-benzomidazol-2-yl]-urea), a potent inhibitor of kinases Aurora A and Aurora B. AT9283 showed potent antiproliferative activity o … More n cells transformed by BCR-ABL/T315I. CMLstem cells also survived in the bone marrow niche under severe hypoxia condition. We generated two hypoxia-adapted(HA)-CML cell lines. These HA-CML cells exhibited stem cell-like characteristics. Compared with the respective parental cells, HA-CML cells had higher levels of protein and higher enzyme activity of glyoxalase-I(Glo-I), that detoxifies methylglyoxal, a cytotoxic by-product of glycolysis. In contrast to Abl TKIs, Glo-I inhibitors were much more effective in killing HA-CML cells both in vitro and in vivo. Ii is likely that leukemic cells are able to survive and proliferate in severely hypoxic environments. The hypoxic conditions allow leukemic cells that reside there to become insensitive to cell death stimuli. To target leukemic cells in hypoxic conditions, we focused on the hypoxia-selective cytotoxin, Rakicidin A. produced by the Micromonospora strain. We describe Rakicidin A-induced cell death in HA-CML cells with stem cell-like characteristics. Rakicidin A is a promising compound for targeting TKI-resistant quiescent CML stem cells in the hypoxic environment. Less