摘要
目的对1例罕见四联染色体变异易位的慢性髓性白血病(chronic myeloid leukemia,CML)患者进行遗传学追踪分析,揭示伴有四联染色体变异易位且合并克隆演变CML患者的临床特性,为患者的治疗选择提供依据。方法应用骨髓细胞形态学、细胞遗传学以及实时定量PCR方法进行诊断和分期,Sanger测序法对ABL1基因酪氨酸激酶区进行变异检测。结果患者起病时为CML慢性期,染色体核型为t(5;9;22;6)(q13;q34;q11;q25),荧光原位杂交检测显示为变异型BCR/ABL1融合信号。经酪氨酸激酶抑制剂(tyrosine kinase inhibitors,TKIs)治疗38个月出现克隆演变,t(5;9;22;6)和t(5;9;22;6;17)(q13;q34;q11;q25;q11)两种克隆并存。TKIs治疗57个月时仅见t(5;9;22;6;17)一种克隆,3个月后出现超二倍体核型。病程中先后检出ABL1基因酪氨酸激酶区p.Tyr253Phe、p.Thr315Ile和p.Gly250Glu型变异,患者始终未能获得细胞遗传学和分子学治疗反应。结论四联染色体变异易位可能具有遗传不稳定性,在TKIs治疗过程中较易出现克隆演变和基因变异,导致对药物治疗反应差,但仍需大宗病例研究证实。
Objective To trace a rare case of chronic myeloid leukemia(CML)with a four-way Philadelphia chromosome variant by cytogenetic analysis in order to provide a basis for the selection of treatment.Methods Bone marrow morphology,chromosomal karyotyping,fluorescence in situ hybridization(FISH)and real-time quantitative PCR(RQ-PCR)were used for the diagnosis and staging of the disease.Point mutations in the tyrosine kinase domain of ABL1 gene were detected by Sanger sequencing.Results The patient was initially diagnosed as CML in chronic phase(CML-CP)with a chromosomal karyotype of 46,XX,t(5;9;22;6)(q13;q34;q11;q25),while FISH revealed presence of a variant Philadelphia chromosome translocation.Clonal evolution has occurred after 38 months of tyrosine kinase inhibitor(TKI)treatment,when cytogenetic analysis revealed coexisting t(5;9;22;6)(q13;q34;q11;q25)and t(5;9;22;6;17)(q13;q34;q11;q25;q11).After 57 months of TKIs treatment,only the t(5;9;22;6;17)clone was detected.Three months later,hyperdiploidy with additional abnormalities were detected in addition to t(5;9;22;6;17).Three mutations,including p.Tyr253Phe,p.Thr315Ile and p.Gly250Glu,were identified in the tyrosine kinase domain of the ABL1 gene during the course of disease.The patient did not attain cytogenetic and molecular response to TKIs.Conclusion The four-way variant translocation may be genetically unstable.Clonal evolution and genetic mutations are likely to occur during TKIs treatment,resulting in poor response to drug therapy.This observation,however,needs to be confirmed by large-scale studies.
作者
孔舒
古雨晴
秦亚溱
王峥
冯麟
江倩
赖悦云
Kong Shu;Gu Yuqing;Qin Yazhen;Wang Zheng;Feng Lin;Jiang Qian;Lai Yueyun(Peking University Institute of Hematology,Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation,Peking University People's Hospital,Beijing 100044,China)
出处
《中华医学遗传学杂志》
CAS
CSCD
2020年第12期1395-1398,共4页
Chinese Journal of Medical Genetics
