Zhou Fen, Jin Runming, Hu Yu, Mei Heng
Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology, 1277 Jiefang Avenue, Wuhan, Hubei 430022 China.
Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei 430022 China.
Mol Cytogenet. 2017 May 19;10:19. doi: 10.1186/s13039-017-0322-8. eCollection 2017.
Chronic myelogenous leukemia (CML) is a pluripotent hematopoietic stem cell disorder caused by the fusion of the and genes. Quantitative RT-PCR (qRT-PCR) is a routinely performed screening technique to identify fusion 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 novel fusion 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.
We here report that using NGS we identified a novel fusion gene with breakpoints in the intron 14 and the intron 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, including , , , , and that seemed to have an influence on the outcome of TKI therapy targeting the BCR-ABL1 protein.
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.
慢性粒细胞白血病（CML）是一种由 和 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反应（qRT-PCR）是一种常规用于鉴定 融合基因的筛查技术，但该方法的一个局限性是无法识别以前未被表征的新型融合基因。下一代测序（NGS）是一种用于确定新型 融合基因以及先前已表征的融合基因的有效且灵敏的检测方法。癌蛋白酪氨酸激酶BCR-ABL1是一种组成型活性激酶，参与多种信号通路的激活，并且一直是伊马替尼等酪氨酸激酶抑制剂（TKIs）的治疗靶点。关于破坏的Src同源3（SH3）结构域对TKI疗效的影响，已有报道提出了相反的观点。
我们在此报告，使用NGS我们鉴定出一种新型 融合基因，其断点位于 内含子14和 内含子2，导致其SH3结构域部分缺失。在本病例中，患者接受了400mg/天的TKI伊马替尼靶向治疗，未报告不良反应。患者最终进入缓解期，核细胞和粒细胞增殖减少。我们还在基因中鉴定出突变，包括 、 、 、 、 和 ，这些突变似乎对靶向BCR-ABL1蛋白的TKI治疗结果有影响。
与先前报道的结果一起，很明显CML患者的基因异质性显著影响疾病的表现及其进展，因此应为治疗策略的设计提供依据。
