FLT3-ITD突变在儿童急性髓性白血病中的表达及其与多药耐药的关系

Expression of FLT3 Internal Tandem Duplication in Pediatric Patients with Acute Myeloid Leukemia and Its Correlation with Multidrug Resistance

为了研究FLT3内部串联重复序列(FLT3-ITD)突变在儿童急性髓系白血病(AML)中的表达、该类患儿的临床特征及其与多药耐药基因mdr1表达的关系,应用RT-PCR技术检测81名初发儿童AML骨髓标本,FLT3-ITD突变及mdr1基因的表达,并分析患儿骨髓细胞遗传学及免疫表型。结果表明:在AML患儿中FLT3-ITD突变率为9.88%(8/81),均为杂合突变。突变患儿年龄较无此突变者明显偏大,但与性别、细胞免疫分型等无关。突变组就诊时白细胞数及骨髓原始细胞数较无突变组显著升高(p=0.001和p=0.041),且突变组患儿表现为正常染色体居多。突变组患儿预后较差,首次诱导缓解率仅为25.00%,而无突变组为76.71%。RT-PCR法检测mdr1基因显示,27名患儿表达该基因,但在FLT3-ITD阳性的8名患儿中只有3人是同时表达mdr1基因,此结果提示FLT3-ITD发生与多药耐药基因的表达无相关性。结论:FLT3-ITD突变是儿童AML中发生频率较高的一类突变,但突变率较成人为低,此类患儿预后差,首次诱导缓解率低,但FLT3-ITD突变与多药耐药基因的表达无相关性,提示耐药调节剂可能对该类患儿无效。

This study was aimed to investigate the expression of FLT3 internal tandem duplication （FLT3-ITD） in pediatric patients with acute myeloid leukemia（AML） and to analyse the clinical features of patients with mutations and the relation of FLT3-ITD with multidrug resistance gene 1 （mdr1）. RT-PCR was used to determine the expressions of FIT3-ITD and mdrl gene in bone marrow samples from 81 new diagnosed pediatric patients with AML, the cytogenetics and immunophenotypes of bone marrow cells were routinely examined. The results indicated that the FLT3-ITDs were detected in 8 out of 81 pediatric patients （9.88%） and all mutations detected were hybrid, while less frequently this mutation was detected in adult patients. Although they were irrelevant with sex and imrnunophenotypes, the mutations seemed predominant in older pediatric patients. The leukocyte counts and bone marrow blast cell counts in pediatric patients with FLT3-ITD at diagnosis were higher than those in pediatric patients without FLT3-ITD （p = 0. 001 and p = 0.041 respectively）, but the normal chromosomes were found in most pediatric patients with FLT-ITD. The patients with FLT3-ITD had lower induction remission rate （ only 25 % ）, but the patients without FLT3-ITD had higher remission rate （76.1% ）. According results detected by RT-PCR, the mdrl gene was found in 27 pediatric patients, but only 3 out of 8 pediatric patients with FLT3-ITD were detected to express both FLT3-ITD and mdrl, which suggests unrelation between FLT3-ITD occurence and mdrl expression. It is concluded that the FLT3-ITD is frequent mutation in pediatric patients with AML, the prognosis is worse and the induction remisson rate is lower in these patients, but the FLT3-ITD not relates with the mdrl, which suggests that the common MDR modolators may be un effective for therapy of the patients with FLT3-ITD.