A novel BCR-ABL1 fusion gene with genetic heterogeneity indicates a good prognosis in a chronic myeloid leukemia case.
A novel BCR-ABL1 fusion gene with genetic heterogeneity indicates a good prognosis in a chronic myeloid leukemia case.
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具有遗传异质性的新型 BCR-ABL1 融合基因表明慢性粒细胞白血病病例预后良好
DOI：
10.1186/s13039-017-0322-8
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发表时间：
2017
影响因子：
1.3
通讯作者：
Mei H
中科院分区：
文献类型：
--
作者：
Zhou F;Jin R;Hu Y;Mei H
背景：慢性粒细胞白血病(CML)是一种由bcr和abl1基因融合引起的多能造血干细胞疾病。定量逆转录聚合酶链式反应(qRT-PCR)是鉴定bcr-abl1融合基因的常规筛选技术，但该方法的局限性在于它不能识别以前尚未鉴定的新融合基因。下一代测序技术(NGS)是一种有效、灵敏的检测新的BCR-ABL1融合基因和已鉴定基因的方法。癌蛋白酪氨酸激酶BCR-ABL1是一种结构性活性蛋白，参与多种信号通路的激活，已成为伊马替尼等酪氨酸激酶抑制剂(TKIs)的治疗靶点。关于中断的Src同源3(SH3)结构域对TKI效应的影响，有报道提出了相反的观点。结果：我们利用NGS发现了一个新的BCR-ABL1融合基因，在BCRinon 14和ABL1内含子2中有断裂点，导致其SH3结构域的部分缺失。在目前的病例中，患者接受了TKI伊马替尼的靶向治疗，每天400毫克，没有报告不良反应。患者最终进入缓解期，有核细胞和粒细胞增殖减少。我们还发现了包括TP53、Flt3、ASXL1、SETBP1、CEBPA和CBL在内的基因突变，这些突变似乎影响了针对BCR-ABL1蛋白的TKI治疗的结果。结论：结合以前报道的结果，CML患者的基因异质性明显影响疾病的表现和进展，因此应为治疗策略的设计提供信息。
Background:Chronic myelogenous leukemia (CML) is a pluripotent hematopoietic stem cell disorder caused by the fusion of theBCRandABL1genes. Quantitative RT-PCR (qRT-PCR) is a routinely performed screening technique to identifyBCR-ABL1fusion genes, but a limitation of this method is its inability to recognize novel fusions that have not been previously characterized. Next-generation sequencing (NGS) is an effective and sensitive detection method for the determination of novelBCR-ABL1fusion genes as well as previously characterized ones. The oncoprotein tyrosine kinase BCR-ABL1 is a constitutively active kinase involved in the activation of a number of signaling pathways, and it has been the therapeutic target for tyrosine kinase inhibitors (TKIs) such as imatinib. Reports have presented opposing viewpoints about the effect of the disrupted Src homology 3 (SH3) domain on TKI efficacy.Findings:We here report that using NGS we identified a novelBCR-ABL1fusion gene with breakpoints in theBCRintron 14 and theABL1intron 2, leading to partial deletion of its SH3 domain. In the present case, the patient received targeted therapy with the TKI imatinib at 400 mg/day and no adverse reaction was reported. The patient eventually entered remission with decreased proliferation of karyocytes and granulocytes. We also identified mutations in genes, includingTP53,FLT3,ASXL1,SETBP1,CEBPAandCBL,that seemed to have an influence on the outcome of TKI therapy targeting the BCR-ABL1 protein.Conclusions:Together with previously reported results, it is clear that the genetic heterogeneity of CML patients significantly affects the presentation of the disease and its progression and therefore should inform the design of the therapeutic strategy.