期刊
BLOOD
卷 107, 期 11, 页码 4532-4539出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2005-07-2947
关键词
-
类别
资金
- MRC [G84/6317] Funding Source: UKRI
- Medical Research Council [G84/6317] Funding Source: researchfish
- Medical Research Council [G84/6317] Funding Source: Medline
- Chief Scientist Office [SCD/04] Funding Source: Medline
Dasatinib (BMS-354825), a novel dual SRC/BCR-ABL kinase inhibitor, exhibits greater potency than imatinib mesylate (IM) and inhibits the majority of kinase mutations in IM-resistant chronic myeloid leukemia (CIVIL). We have previously demonstrated that IM reversibly blocks proliferation but does not induce apoptosis of primitive CIVIL cells. Here, we have attempted to overcome this resistance with dasatinib. Primitive IM-resistant CML cells showed only single-copy BCR-ABL but expressed significantly higher BCR-ABL transcript levels and BCR-ABL protein compared with more mature CML cells (P = .031). In addition, CrKL phosphorylation was higher in the primitive CD34(+)CD38(-) than in the total CD34(+) population (P = .002). In total CD34(+) CIVIL cells, IM inhibited phosphorylation of CrKL at 16 but not 72 hours, consistent with enrichment of an IM-resistant primitive population. CD34(+)CD38(-) CML cells proved resistant to IM-induced inhibition of CrKL phosphorylation and apoptosis, whereas dasatinib led to significant inhibition of CrKL phosphorylation. Kinase domain mutations were not detectable in either IM or dasatinib-resistant primitive CML cells. These data confirm that dasatinib is more effective than IM within the CML stem cell compartment; however, the most primitive quiescent CML cells appear to be inherently resistant to both drugs.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据