FLT3 mutations in the activation loop of tyrosine kinase domain are frequently found in infant ALL with MLL rearrangements and pediatric ALL with hyperdiploidy
FLT3 mutations in the activation loop of tyrosine kinase domain are frequently found in infant ALL with MLL rearrangements and pediatric ALL with hyperdiploidy
复制标题
DOI：
10.1182/blood-2003-02-0418
复制
发表时间：
2004-02-01
期刊：
影响因子：
20.3
通讯作者：
Hayashi, Y
中科院分区：
文献类型：
--
作者：
Taketani, T;Taki, T;Hayashi, Y
FLT3 基因 D835/I836 点突变已在成人急性髓性白血病 (AML) 中报道，但在儿童 AML 或急性淋巴细胞白血病 (ALL) 中未见报道。在 112 名 1 岁以上 ALL 儿童中，有 6 名 (5.4%) 发现了 FLT3-D835/I836 突变，在 50 名 ALL 婴儿中，有 8 名 (16.0%) 发现了 FLT3-D835/I836 突变。 11 名患者发现错义突变，2 名患者发现 3 碱基对缺失，1 名患者发现缺失/插入。值得注意的是，在 44 名患有 MLL 重排的 ALL 婴儿中，有 8 名 (18.2%) 发现了 FLT3-D835/I836 突变，在 19 名超二倍体 ALL 患者中，有 4 名 (21.5%) 发现了 FLT3-D835/I836 突变，但在 1 岁以上患有 TEL-AML1 (n = 11)、E2A-PBX1 (n = 4) 或 BCR-ABL 的患者中未发现 FLT3-D835/I836 突变。 (n = 6) 融合基因。尽管携带突变的婴儿 ALL 患者的预后比未携带突变的患者较差，但 1 岁以上携带突变的儿科 ALL 患者的预后良好。我们还在 11 个具有 MLL 重排的白血病细胞系中的 2 个中发现了 FLT3-D835 突变。 FLT3 在这些具有 FLT3-D835 突变的细胞系中高度磷酸化，导致下游靶标的组成型激活，例如信号转导子和转录激活子 5 (STAT5)，而无需 FLT3 配体刺激。这些结果表明，FLT3-D835/1836 突变是具有 MLL 重排的婴儿 ALL 或具有超二倍体的儿童 ALL 的第二个遗传事件之一。
Point mutations of D835/I836 of the FLT3 gene have been reported in adult acute myeloid leukemia (AML), but not in pediatric AML or acute lymphoblastic leukemia (ALL). FLT3-D835/I836 mutations were found in 6 (5.4%) of 112 children with ALL older than 1 year and in 8 (16.0%) of 50 infants with ALL. Missense mutations were found in 11 patients, 3-base pair deletions in 2 patients, and a deletion/ insertion in 1 patient. Remarkably, FLT3-D835/I836 mutations were found in 8 (18.2%) of 44 infants with ALL with MLL rearrangements and in 4 (21.5%) of 19 patients with hyperdiploid ALL, but they were not found in any patients older than 1 year who had TEL-AML1 (n = 11), E2A-PBX1 (n = 4), or BCR-ABL (n = 6) fusion genes. Although infant ALL patients with mutations had poorer prognoses than did those without mutations, pediatric ALL patients with mutations who were older than 1 year had good prognoses. We also found FLT3-D835 mutations in 2 of 11 leukemic cell lines with MLL rearrangements. FLT3 was highly phosphorylated in these cell lines with FLT3-D835 mutations, leading to constitutive activation of downstream targets such as signal transducer and activator of transcription 5 (STAT5) without FLT3 ligand stimulation. These results suggested that FLT3-D835/ 1836 mutations are one of the second genetic events in infant ALL with MLL rearrangements or pediatric ALL with hyperdiploidy.