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A novel mutation of receptor tyrosine kinase gene, closely associated with leukemic transformation of myelodysplastic syndrome

受体酪氨酸激酶基因新突变与骨髓增生异常综合征白血病转化密切相关

基本信息

批准号：
09671128
负责人：
HORIIKE Shigeo
金额：
$ 0.9万
依托单位：
Kyoto Prefectural University of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1999
项目状态：
已结题

项目摘要

We carried out a screening analysis for internal tandem duplication of the FLT3 receptor gene (FLT3-ITD) in 180 patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS), and found several clinical characteristics as follows :(1) FLT3-ITDs were identified in approximately 5% of patients with MDS, and were found more frequently in acute leukemia (20%). Mutant mRNA was expressed in all cases examined. In MDS, the frequency was higher in subtypes with excess of immature blasts, and we conclusively presume that this mutation is closely associated with leukemic transformation from MDS.(2) Longitudinal analyses of the FLT3 gene configuration revealed that FLT3-ITD was late genetic alteration during the clinical course of MDS, as well as an N-RAS mutation. And these alterations did not show a relationship to specific chromosomal abnormalities.(3) Among receptor tyrosine kinase type III genes (FLT3, KIT, PDGFR and CSF1R), the FLT3 gene solely showed ITDs in its juxtamembrane domain. And this novel type of mutation may positively influence proliferation of leukemic or myelodysplastic cells through elevation of kinase activity, based on undetermined mechanisms.(4) The primers containing case-specific DNA sequences, generated by FLT3-ITD, allow us to amplify mutant FLT3 gene, resulting in appropriate detection of minimal residual disease in bone marrow samples or peripheral blood stem cells.(5) Although the molecular basis of FLT3-ITD is not known well, the clinical manifestation of AML patients with mutant FLT3 was well delineated, and those with this alteration were revealed to show poor prognosis.Further investigations are preferred to establish clinical and biological significance of this novel mutational event.

我们对180例急性髓性白血病（AML）或骨髓增生异常综合征（MDS）患者进行了FLT3受体内串联重复基因（FLT3- itd）的筛选分析，发现了以下几个临床特征：(1)FLT3- itd在约5%的MDS患者中被发现，在急性白血病中更常见（20%）。所有病例均表达突变mRNA。在MDS中，在未成熟细胞过多的亚型中，这种频率更高，我们最终假设这种突变与MDS的白血病转化密切相关。(2) FLT3基因构型的纵向分析显示，FLT3- itd是MDS临床过程中的晚期遗传改变，同时也是N-RAS突变。这些改变并没有显示出与特定染色体异常的关系。(3)受体酪氨酸激酶III型基因（FLT3、KIT、PDGFR和CSF1R）中，FLT3基因仅在其近膜结构域出现ITDs。这种新型突变可能通过激酶活性的升高对白血病或骨髓增生异常细胞的增殖产生积极影响，其机制尚不确定。(4)由FLT3- itd产生的含有病例特异性DNA序列的引物，使我们能够扩增突变的FLT3基因，从而在骨髓样本或外周血干细胞中适当检测微量残留疾病。(5)虽然FLT3- itd的分子基础尚不清楚，但FLT3突变的AML患者的临床表现已被很好地描绘出来，有这种改变的患者预后较差。进一步的研究更倾向于确定这种新型突变事件的临床和生物学意义。