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

甲磺酸伊马替尼(IM，GleevecR)特异性地抑制Abl酪氨酸激酶(TK)的自磷酸化，极大地改善了慢性粒细胞白血病(CML)的治疗。然而，抗药性经常在晚期疾病患者中报告。一些新的第二代TK抑制剂(TKI)已经被开发出来，如达沙替尼(SprycelR)、尼洛替尼(TasignaR)和INNO-406(Bafetinib)，它们可以覆盖由Abl激酶结构域内的点突变引起的IM耐药机制。因为与IM相比，这些新的TKI对ATP结合位点有很强的亲和力，所以这些新的TKI可能对IM抵抗的患者有效。但不能抑制苏氨酸315突变为异亮氨酸的T315I bcr-Abl的磷酸化。AT9283(1-环丙基-3[5-吗啉-4YL甲基-1H-苯并咪唑-2-基]尿素)是一种有效的Aurora A和Aurora B酶抑制剂，对…有很强的抗增殖活性。BCR-ABL/T315I转化的n细胞数较多。在严重缺氧条件下，CML干细胞也能在骨髓巢中存活。我们建立了两个低氧适应(HA)-CML细胞系。这些HA-CML细胞表现出干细胞样特征。与亲本细胞相比，HA-CML细胞具有更高的蛋白质水平和更高的乙草酸酶-I(Glo-I)活性，该酶可解毒糖酵解的细胞毒性副产物甲乙醛。与Abl TKI相比，Glo-I抑制剂在体外和体内对HA-CML细胞的杀伤作用都要强得多。白血病细胞很可能能够在严重缺氧的环境中存活和增殖。低氧条件使居住在那里的白血病细胞对细胞死亡刺激变得不敏感。为了针对低氧条件下的白血病细胞，我们重点研究了小单孢菌产生的低氧选择性细胞毒素Rakicidin A。我们描述了Rakicidin A诱导具有干细胞样特征的HA-CML细胞的细胞死亡。Rakicidin A是一种在低氧环境中靶向抗TKI静止期CML干细胞的有前景的化合物。较少

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