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首页> 外文期刊>The Lancet >Relation between resistance of Philadelphia-chromosome-positive acute lymphoblastic leukaemia to the tyrosine kinase inhibitor STI571 and gene-expression profiles: a gene-expression study.
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Relation between resistance of Philadelphia-chromosome-positive acute lymphoblastic leukaemia to the tyrosine kinase inhibitor STI571 and gene-expression profiles: a gene-expression study.

机译：费城染色体阳性急性淋巴细胞白血病对酪氨酸激酶抑制剂STI571的耐药性与基因表达谱之间的关系：一项基因表达研究。

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摘要

BACKGROUND: The ABL tyrosine kinase inhibitor STI571 is a promising agent for treatment of advanced Philadelphia-chromosome-positive (Ph+) acute lymphoblastic leukaemia. However, resistance to this drug develops within a few months in most patients. We aimed to predict resistance to STI571. METHODS: Total RNA was extracted from 25 bone-marrow samples from 19 patients with Ph+ acute lymphoblastic leukaemia who were enrolled into a phase II study. 17 samples were obtained before STI571 treatment was started: ten from individuals who were classified as good responders to STI571 (sensitive), and seven from individuals who did not to respond to STI571 (primary resistance). Eight samples were obtained from patients during treatment with STI571. We analysed six matched samples, which were obtained before and during treatment with STI571. Oligonucleotide microarray analysis of samples was done with high-density microarrays. FINDINGS: We identified 95 genes whose expression could be used to predict sensitivity of leukaemic cells to STI571. On this basis, all the STI571-sensitive samples could clearly be distinguished from the resistant cases. 56 highly differentially expressed genes were identified in leukaemic cells that were secondarily resistant to STI571. Resistant leukaemic cells expressed high levels of Bruton's tyrosine kinase and two ATP synthetases (ATP5A1 and ATP5C1), and showed significantly reduced expression of the proapoptotic gene BAK1 and the cell-cycle control gene p15 INK4b. INTERPRETATION: We have shown the clinical relevance of gene expression data for the pretreatment assessment of acute lymphoblastic leukaemia. Our results have implications for future clinical studies of tyrosine kinase inhibitors.
机译：背景：ABL酪氨酸激酶抑制剂STI571是用于治疗晚期费城染色体阳性（Ph +）急性淋巴细胞白血病的有前途的药物。但是，在大多数患者中，对这种药物的耐药性会在几个月内形成。我们旨在预测对STI571的抵抗力。方法：从19例Ph +急性淋巴细胞白血病患者的25份骨髓样本中提取总RNA，该患者参加了II期研究。在开始进行STI571治疗之前已获得17个样本：十个来自被分类为对STI571良好应答（敏感）的个体，七个来自不对STI571产生应答（原发性耐药）的个体。在用STI571治疗期间从患者获得了八个样本。我们分析了六个匹配的样本，这些样本是在用STI571治疗之前和期间获得的。样品的寡核苷酸微阵列分析使用高密度微阵列进行。结果：我们鉴定了95个基因，这些基因的表达可用于预测白血病细胞对STI571的敏感性。在此基础上，可以将所有STI571敏感样品与抗药性样品区分开。在白血病细胞中鉴定出56个高度差异表达的基因，这些基因继发于STI571。耐药性白血病细胞表达高水平的布鲁顿酪氨酸激酶和两种ATP合成酶（ATP5A1和ATP5C1），并显示凋亡基因BAK1和细胞周期控制基因p15 INK4b的表达显着降低。解释：我们已经显示了基因表达数据与急性淋巴细胞白血病的治疗前评估的临床相关性。我们的结果对酪氨酸激酶抑制剂的未来临床研究具有影响。

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