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背景与目的:Flt-3跨膜区内部串联重复(Flt-3internaltandemduplication,Flt-3/ITD)突变是近年来发现的Flt-3基因最常见的一种突变类型,是急性髓系白血病(acutemyeloidleukaemia,AML)中发生率最高且与预后相关的突变。本研究旨在探讨Flt-3/ITD突变与儿童白血病发生的关系及其临床意义。方法:采用聚合酶链反应(polymerasechainreaction,PCR)联合序列测定,检测302例儿童白血病患者骨髓Flt-3/ITD突变情况,其中包括AML122例、急性淋巴细胞白血病(acutelymphoblasticleukemia,ALL)124例、幼年型慢性粒细胞白血病(juvenilechronicmyelogenousleukemia,JCML)17例和骨髓异常增生综合征(myelodysplasticsyndromes,MDS)39例。结果:122例AML患者中98例(80.33%)Flt-3阳性;21例(17.21%)发生Flt-3/ITD突变,分别为M03例、M12例、M24例、M48例及M54例,突变率分别为42.86%(3/7)、22.22%(2/9)、12.90%(4/31)、44.44%(8/18)和15.38%(4/26)。此外,124例ALL中72例Flt-3阳性,阳性率为58.06%,其中2例发现Flt-3/ITD突变,突变率1.61%。测序及Blast比对分析显示,外显子11区均有ITD,各例ITD的复制区域不同,长短不等(24～95bp)。39例MDS和17例JCML患者中均未检测到Flt-3/ITD突变。临床资料显示,21例Flt-3/ITD突变的AML患者中有19例在短期内死亡,这19例的中位生存时间为13.5个月(0～47个月),死亡率为90.48%,与无Flt-3/ITD突变患者相比有显著性差异(P<0.05)。Flt-3/ITD突变阳性患者外周血中性粒细胞平均比率与Flt-3/ITD突变阴性患者无显著性差异(P>0.05)。染色体核型分析显示,Flt-3/ITD的AML患者中3例存在有染色体异位,分别为t(11;12)(p15;q13)、t(6;9)(p23;q23)、inv16(q21;q23)。结论:Flt-3/ITD突变多发现于AML,罕见于ALL,未见于MDS和JCML。该突变与儿童白血病特别是儿童AML的发生及进展有关。Flt-3/ITD可以作为判断AML预后的重要标志之一。
BACKGROUND & OBJECTIVE: Flt-3internal tandem duplication (Flt-3 / ITD) mutation in the Flt-3 transmembrane region is one of the most common type of Flt-3gene mutations found in recent years. It is a type of acute myeloid leukemia (acutemyeloid leukemia, AML) the highest incidence and prognosis-related mutations. This study aimed to investigate the relationship between the Flt-3 / ITD mutation and childhood leukemia and its clinical significance. Methods: The mutations of Flt-3 / ITD in 302 children with childhood leukemia were detected by polymerase chain reaction (PCR) and sequencing, including 122 cases of AML, 124 cases of acute lymphoblastic leukemia (ALL), juvenile 17 cases of juvenile chronic myelogenous leukemia (JCML) and 39 cases of myelodysplastic syndromes (MDS). Results Flt-3 was positive in 98 cases (80.33%) of 122 AML patients and Flt-3 / ITD mutations in 21 cases (17.21%), including M03 cases, M12 cases, M24 cases, M48 cases and M54 cases Rates were 42.86% (3/7), 22.22% (2/9), 12.90% (4/31), 44.44% (8/18) and 15.38% (4/26), respectively. In addition, 72 of 124 ALL cases were positive for Flt-3, the positive rate was 58.06%. Two of them found Flt-3 / ITD mutation with a mutation rate of 1.61%. Sequencing and Blast analysis showed that there were ITDs in exon 11 and different regions of ITD in different cases, ranging in length from 24 to 95bp. No Flt-3 / ITD mutation was detected in 39 cases of MDS and 17 cases of JCML. According to clinical data, 19 of 21 patients with Flt-3 / ITD mutations died within a short period of time. The median survival time of these 19 patients was 13.5 months (0-47 months) with a mortality rate of 90.48% There was a significant difference (P <0.05) between patients with and without Flt-3 / ITD mutation. The average ratio of peripheral blood neutrophils in Flt-3 / ITD mutation-positive patients was not significantly different from that in Flt-3 / ITD mutation negative patients (P> 0.05). Chromosomal karyotype analysis showed that 3 cases of AML patients with Flt-3 / ITD had chromosomal abnormalities of t (11; 12) (p15; q13), t (6; 9) (q21; q23). Conclusion: Flt-3 / ITD mutations were found in AML, rare in ALL, but not in MDS and JCML. This mutation is associated with the occurrence and progression of childhood leukemia, especially childhood AML. Flt-3 / ITD can be used as one of the important markers to judge the prognosis of AML.