伴不典型BCR-ABL融合基因的慢性髓性白血病的临床和实验研究  

A clinical and laboratory study of chronic myeloid leukemia with atypical BCR-ABL fusion gene subtypes

作　　者：桂晓敏[1] 潘金兰[1] 仇惠英[1] 岑建农[1] 薛永权[1] 陈苏宁[1] 沈宏杰[1] 姚利[1] 张俊[1] 吴亚芳[1] 陈艳[1] 

机构地区：[1]苏州大学附属第一医院、江苏省血液研究所,215006

出　　处：《中华血液学杂志》2014年第3期210-214,共5页Chinese Journal of Hematology

基　　金：国家自然科学基金（青年自然科学基金）（81100332）

摘　　要：目的探讨伴不典型BCR-ABL融合基因亚型e14a3和e19a2型慢性髓性白血病（cML）的临床和实验室特点。方法对2004至2012年染色体核型分析有t（9；22）（q34；q11），荧光原位杂交（FISH）证实为BCR-ABL融合基因阳性，而常规实时定量PCR（RQ．PCR）检测常见BCR—ABL融合基因（b3a2、b2a2和ela2）阴性的6例CML患者，重新设计引物进行PCR扩增，并将扩增产物测序，以明确不典型BCR-ABL融合基因类型。对BCR．ABL融合基因扩增产物进行突变检测。对患者的临床资料进行回顾性分析。结果6例患者PCR扩增产物经测序分析，其中5例为e14a3型，1例为e19a2型。5例e14a3型CML患者中，男4例，女1例，中位年龄48岁，慢性期4例，加速期1例；1例e19a2型患者为女性，40岁，CML慢性期，PLT〉1000×10^9／L。5例e14a3型CML患者中4例在羟基脲或IFN治疗无效后予以伊马替尼（IM）治疗，1例行造血干细胞移植（HSCT）。前4例患者中1例因有E255K突变而对IM耐药，改用达沙替尼后获完全细胞遗传学反应（CCyR）；1例在IM治疗获CCyR后3个月复发并急变，最终死亡；2例IM治疗后获CCyP．目前状态稳定，仍处于CCyR，尽管其中1例伴有1293T突变。行HSCT治疗患者目前处于CCyR。1例e19a2型CML患者羟基脲治疗后获得完全血液学反应，后改用IM治疗，很快获得CCyR。结论伴不典型BCR-ABL融合基因的CML发病率极低，酪氨酸激酶抑制剂或HSCT都可以取得疗效，常规RQ-PCR可能漏检少见的不典型BCR-ABL融合基因亚型。Objective To explore the clinical and laboratory features of chronic myeloid leukemia （CML） with atypical e14a3 and e19a2 BCR-ABL fusion gene subtypes. Methods We retrospectively analyzed a cohort of CML patients with Ph chromosome positive confirmed by cytogenetic and FISH but classical e13a3 （b2a2）, e14a2 （b3a2） and ela2 fusion transcripts negative identified by conventional real- time quantification RT-PCR （RQ-PCR）. Further RQ-PCR was done with the forward primer and reverse primer designed to detect rare atypical BCR-ABL fusion genes including e14a3 and e19a2 transcripts. Direct sequencing analysis was performed on the PCR products and mutations in the BCR-ABL kinase domain were detected. The clinical data of patients were retrospectively analyzed. Results Six CML patients were found to carry t （9;22） abnormality and BCR-ABL rearrangement confirmed by FISH but classical BCR-ABL fusion genes negative detected by RQ-PCR. Further RQ-PCR and sequencing analysis confirmed the fusion of BCR exon 14 and ABL exon 3 in five CML patients （casel-5） and the fusion of BCR exon 19 and ABL exon 2 in one CML patient （case 6）. E255K and I293T IM-resistant mutations were detected in case 1 and 2, respectively. Among five cases with e14a3 transcripts, four were CML-CP, one CML-AP. Four patients were male and one was female. The median age was 48 years. The patient （case 6） with e19a2 transcripts was 40-year-old female with a diagnosis of CML-CP and PLT count was more than 1 000x 109/L. Imatinib （IM） therapy was administed in case 1, 2, 3, 4 and hematopoietic stem cell transplantation （HSCT） was undergone in case 5 after hydroxyurea （Hu） or interferon failure. Case 1 who had E255K IM resistant mutation, responded poorly to IM but obtained a complete cytogenetic remission （CCyR） after a substitution of dasatinib for IM. Case 2 and 3 achieved CCyR 6 months later after IM treatment and had been maintained well with IM despite I293T mutation in case 2. Case 4 attained CCyR 3 months lat

关 键 词：白血病 髓样 慢性 伊马替尼 

分 类 号：R733.72[医药卫生—肿瘤]