Tandem duplications of the FLT3 receptor gene are associated with leukemic transformation of myelodysplasia
Tandem duplications of the FLT3 receptor gene are associated with leukemic transformation of myelodysplasia
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DOI：
10.1038/sj.leu.2400770
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发表时间：
1997-09-01
期刊：
影响因子：
11.4
通讯作者：
Misawa, S
中科院分区：
文献类型：
--
作者：
Horiike, S;Yokota, S;Misawa, S
我们最近报道了17%的急性髓细胞性白血病（AML）的人flt 3受体基因（FLT 3）的内部串联重复作为体细胞突变。本研究揭示了在骨髓增生异常综合征（MDS）和AML伴三系骨髓增生异常（AML/TMDS）的92例患者中的7例（8%）中FLT 3的胞膜和第一酪氨酸激酶结构域的重复，这些疾病可能代表多能干细胞的肿瘤性变化。58例MDS患者中有2例（3%）和34例显性白血病（包括MDS衍生性白血病、AML/TMDS和治疗相关性白血病）患者中有5例（15%）存在FLT 3外显子II的串联重复。尽管在每种情况下，重复区域在外显子id内各不相同，但它们都发生在读码框内，逆转录聚合酶链反应证实了mRNA表达的改变。两例FLT 3重复的MDS在几个月内转化为明显的白血病。对另外两名白血病患者的纵向分析显示，重复是疾病过程中的晚期遗传事件;其中一名患者在终末耐药期显示出两个独立的FLT 3重复。在7例FLT 3重复的患者中，6例有异常核型，4例携带N-RAS和/或TP 53基因的点突变。这项研究揭示了这样一个事实，即遗传事件的积累，包括FLT 3复制，与白血病从先前的骨髓增生异常转化和随后的疾病进展相关。
We recently reported an internal tandem duplication of the human flt3 receptor gene (FLT3) as a somatic mutation in 17% of acute myelogenous leukemia (AML). The present study revealed the duplication at the juxtamembrane and the first tyrosine kinase domains of FLT3 in seven of 92 (8%) patients with myelodysplastic syndrome (MDS) and AML with trilineage myelodysplasia (AML/TMDS), the diseases which may represent neoplastic, changes of pluripotent stem cells. A tandem duplication of exon II of FLT3 was harbored by two of 58 (3%) patients with MDS and five of 34 (15%) with overt leukemia, including MDS-derived leukemia, AML/TMDS and therapy-related leukemia, Although the duplicated regions varied within exon id in each case, they occurred in-frame, and altered mRNA expressions were demonstrated by reverse-transcription polymerase chain reaction. Two Gases of MDS with a FLT3 duplication transformed to overt leukemia within a few months. Longitudinal analyses in two other patients with leukemia revealed that the duplication was a late genetic event during the disease course; one of whom showed two independent duplications of FLT3 al the terminal therapy-resistant phase. Of seven patients with the FLT3 duplication, six had abnormal karyotypes, and four harbored a point mutation of the N-RAS and/or TP53 genes, Patients with FLT3 mutations have poor prognoses. This study uncovered the fact that the accumulation of genetic events, including FLT3 duplication, correlates with leukemic transformation from antecedent myelodysplasia and with subsequent disease progression.