Exon 7 Deletion in the bcr-abl Gene Is Frequent in Chronic Myeloid Leukemia Patients and Is Not Correlated with Resistance against Imatinib
Exon 7 Deletion in the bcr-abl Gene Is Frequent in Chronic Myeloid Leukemia Patients and Is Not Correlated with Resistance against Imatinib
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DOI：
10.1158/1535-7163.mct-10-0595
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发表时间：
2010-11-01
影响因子：
5.7
通讯作者：
Lavabre-Bertrand, Thierry
中科院分区：
文献类型：
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作者：
Gaillard, Jean-Baptiste;Arnould, Cecile;Lavabre-Bertrand, Thierry
接受伊马替尼治疗的慢性粒细胞白血病(CML)患者出现频繁的耐药性，通常是由于点突变。最近，ABL序列的大规模重排也被描述出来。在这项研究中，我们重点研究了外显子7的完全缺失。我们通过高分辨熔融(HRM)分析和直接测序对63例耐药患者进行了bcr-abl(Delexon 7)的筛查。此外，我们通过定量聚合酶链式反应或片段长度分析，分析了17例初诊CML患者、32例耐药患者和20例阴性对照中ABL(Delexon 7)和bcr-abl(Delexon 7)的表达。在63例耐药患者中，HRM检出34例(54%)bcr-abl基因，直接测序仅检出3.2%，表明筛查敏感性提高。该缺失与点突变无关(P=0.3362)。此外，在所有具有相同表达模式的测试样本中都发现了ABL(Delexon7)，这表明了一种替代的剪接机制。在bcr-abl组分中，初诊CML患者与耐药患者的bcr-abl比例差异无统计学意义(P=0.2815)，不支持缺失参与耐药。此外，在两名确诊时携带bcr-abl(外显子7)的患者中，一名患者经历了该转录本的完全消失，另一名患者在耐药时下降了75%。总之，在使用敏感技术时，CML患者中经常可以观察到bcr-abl(基因第7外显子)。它似乎是另一种剪接机制的结果，与耐药性的发生无关。摩尔癌症治疗；9(11)；3083-9。(C)2010年AACR。
Chronic myeloid leukemia (CML) patients treated with imatinib develop frequent resistance generally due to a point mutation. Recently, large rearrangements of abl sequence have also been described. In this study, we focused on the complete deletion of exon 7. We screened for bcr-abl(delexon7) in 63 resistant patients by high-resolution melting (HRM) analysis and direct sequencing. Moreover, we analyzed expression of abl(delexon7) and bcr-abl(delexon7) in 17 CML patients at diagnosis, 32 patients at resistance, and 20 negative controls by quantitative PCR or fragment length analysis. bcr-abl(delexon7) was detected on 34 (54%) among 63 resistant patients by HRM, showing an increase in the sensitivity of screening, because only 3.2% could be detected by direct sequencing. This deletion was not associated with a point mutation (P = 0.3362). In addition, abl(delexon7) was found in all tested samples with the same pattern of expression, suggesting an alternative splicing mechanism. In the bcr-abl component, there was no statistical difference between CML patients at diagnosis and resistant patients (P = 0.2815) as regarding bcr-abl(delexon7) proportion, thus arguing against involvement of deletion in resistance. Moreover, among two patients harboring bcr-abl(delexon7) at diagnosis, one experienced a complete disappearance of this transcript, and the other decreased > 75% at resistance. In conclusion, bcr-abl(delexon7) is frequently observed in CML patients when using sensitive techniques. It seems to be the result of an alternative splicing mechanism and to be independent from the occurrence of resistance. Mol Cancer Ther; 9(11); 3083-9. (C) 2010 AACR.