BCR-ABL nuclear entrapment kills human CMIL cells: ex vivo study on 35 patients with the combination of imatinib mesylate and leptomycin B
BCR-ABL nuclear entrapment kills human CMIL cells: ex vivo study on 35 patients with the combination of imatinib mesylate and leptomycin B
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DOI：
10.1182/blood-2005-05-2123
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发表时间：
2006-02-15
期刊：
影响因子：
20.3
通讯作者：
Vigneri, P
中科院分区：
文献类型：
--
作者：
Aloisi, A;Di Gregorio, S;Vigneri, P
慢性粒细胞白血病(CML)bcr-abl癌蛋白定位于细胞质，激活增殖和抗凋亡信号通路。我们先前报道，ABL激酶抑制剂甲磺酸伊马替尼(IM)和核出口抑制剂瘦素8(LMB)联合作用可将BCR-ABL困在细胞核内，从而触发白血病细胞的死亡。为了评价IM和LMB联合应用对人类细胞的影响，我们收集了6名健康献血者的CD34阳性细胞和35例CML患者的髓系祖细胞。IM和LMB的顺序添加对白血病细胞的增殖能力产生了最强烈的抑制作用，对正常髓系前体细胞的毒性有限。此外，对每种实验条件下的克隆进行巢式逆转录聚合酶链式反应(RT-PCR)分析表明，IM和LMB的组合是减少bcr-abl阳性克隆数量的最有效方案。两药联合的疗效与患者的临床特征无关。我们的结果表明，针对bcr-abl核包裹的策略有效地杀灭了人类白血病细胞，这表明该方法的临床发展对新诊断的和IM耐药的CML患者具有重要的治疗价值。
The BCR-ABL oncoprotein of chronic myelogenous leukemia (CML) localizes to the cell cytoplasm, where it activates proliferative and antiapoptotic signaling pathways. We previously reported that the combination of the ABL kinase inhibitor imatinib mesylate (IM) and the nuclear export inhibitor leptomycin 8 (LMB) traps BCR-ABL inside the nucleus, triggering the death of the leukemic cells. To evaluate the efficacy of the combination of IM and LMB on human cells we collected CD34-positive cells from 6 healthy donors and myeloid progenitors from 35 patients with CML. The sequential addition of IM and LMB generated the strongest reduction in the proliferative potential of the leukemic cells, with limited toxicity to normal myeloid precursors. Furthermore, nested reverse transcriptase-polymerase chain reaction (RT-PCR) analysis on colonies representative of each experimental condition demonstrated that the combination of IM and LMB was the most effective regimen in reducing the number of BCR-ABL-positive colonies. The efficacy of the 2-drug association was independent of the clinical characteristics of the patients. Our results indicate that strategies aimed at the nuclear entrapment of BCR-ABL efficiently kill human leukemic cells, suggesting that the clinical development of this approach could be of significant therapeutic value for newly diagnosed and IM-resistant CML patients.