SET-NUP214融合基因阳性儿童白血病/淋巴瘤Ig/TR基因重排模式及其临床特征

Gene Rearrangement Pattern of Immunoglobulin and T-cell Receptor(Ig/TR) and Its Clinical Characteristics in Children with SET-NUP214 Fusion Gene-Positive Leukemia/Lymphoma

为分析3例少见SET-NUP214融合基因阳性儿童免疫球蛋白和T细胞受体基因(Ig/TR)重排模式及其临床特征,采用逆转录巢式聚合酶链反应(RT-nested PCR)检测SET-NUP214融合基因表达;采用欧洲BIOMED-2协作组设计的多重PCR体系,分析Ig/TR重排模式,并根据连接区序列设计特异性引物监测微小残留病(MRD)。结果表明,在mRNA水平3例患儿融合基因的融合位点位SET基因的第7外显子和NUP214基因的第18外显子之间。3例患儿分别诊断为混合表型急性白血病(MPAL,患儿1)、急性T淋巴细胞白血病(T-ALL,患儿2)和Ⅳ期T淋巴母细胞淋巴瘤(T-LBL,患儿3)。患儿1治疗反应极差,在造血干细胞移植后6个月复发;患儿2在诱导缓解治疗结束时(第33天)MRD>10-2,提示预后较差,在巩固治疗期死于中毒性表皮坏死溶解症导致的严重感染;患儿3在第15天时即获得血液学完全缓解(CR),第33天时MRD转阴,CR已30个月。3例患儿均检出TR基因克隆性重排,患儿1和患儿3检出TRD、TRG、TRB基因重排;患儿2只有TRD、TRB基因重排,还检出IgH以及IgKKde重排。3例患儿共检出6个TRB基因重排,均为不完全重排;TRD、TRG基因重排中,85.7%(6/7)为完全重排,14.3%(1/7)为不完全重排。结论:SET-NUP214+白血病/淋巴瘤细胞发生恶性转化的阶段可能在TRG、TRD基因重排之后、TRB基因重排开始不久。患儿1、患儿2的肿瘤细胞的不成熟程度较高,可能与预后或治疗反应差存在一定相关性。

The purpose of this study was to analyze the gene rearrangement pattern of immunoglobulin and T-cell receptor（Ig/TR） and its clinical characteristics in three children with SET-NUP214 fusion gene positive leukemia/lymphoma.The transcript of SET-NUP214 fusion gene was detected by RT-nested PCR.The pattern of Ig/TR gene rearrangement was analyzed by using the BIOMED-2 multiplex PCR assays.Allelic-specific primers were designed for further monitoring the minimal residual disease（MRD）.The results indicated that the fusion site located between exon 7 of SET and exon 18 of NUP214 at mRNA level in the three patients.The diagnoses were made as the mixed phenotype of acute leukemia（MPAL） for patients 1,acute T-lymphoblastic leukemia（T-ALL） for patients 2,and stage Ⅳ T-lymphoblastic lymphoma（T-LBL） for patients 3,respectively.Patient 1 responded to chemotherapy very poorly and relapsed at month 6 after hematopoietic stem cell transplantation.Patient 2 had high MRD（〉10^-2） at the end of inducing remission therapy（day 33） which implied poor outcome,and died of toxic epidermal necrolysis and sequent serious infection.Patient 3 achieved hematological complete remission（CR） and MRD negative at day 15 and day 33 respectively.The duration of CR lasted for 30 months.Clonal TR gene rearrangements were detected in all the three patients.The rearrangements of TRD,TRG and TRB were found in patient 1 and 3.The rearrangements of TRD,TRB,IgH and IgK Kde were detected in patient 2.All the 6 TRB rearrangements detected were incomplete rearrangements,whereas 85.7% and 14.3% of the TRD,and TRG rearrangements were complete and incomplete,respectively.It is concluded that the transformation of SET-NUP214^＋ leukemia/lymphoma cells may occur after the rearrangements of TRD and TRG and shortly after TRB rearrangement.The leukemia/lymphoma cells of patient 1 and 2 are more immature which may be related with poor outcome or response to chemotherapy.