Dual mutations in the AML1 and FLT3 genes are associated with leukemogenesis in acute myeloblastic leukemia of the M0 subtype
Dual mutations in the AML1 and FLT3 genes are associated with leukemogenesis in acute myeloblastic leukemia of the M0 subtype
复制标题
DOI：
10.1038/sj.leu.2403160
复制
发表时间：
2003-12-01
期刊：
影响因子：
11.4
通讯作者：
Asou, N
中科院分区：
文献类型：
--
作者：
Matsuno, N;Osato, M;Asou, N
转录因子AML1的点突变与急性髓细胞白血病（AML）的白血病发生有关。AML中最常见的遗传学改变是Fms样酪氨酸激酶3（FLT3）基因的内膜结构域的内部串联重复（ITD）和第二个酪氨酸激酶结构域的突变。然而，这种突变本身似乎不足以导致白血病转化。为了评估AML 1和FLT3突变是否有助于白血病发生，我们分析了AML M0亚型中这些基因的突变，其中主要观察到AML 1突变。在51例患者中，8例显示AML 1基因Runt结构域突变：1例杂合错义突变，功能正常，5例杂合移码突变和2例双等位基因无义或移码突变，导致AML 1活性单倍不足或完全丧失。另一方面，在49名接受检查的患者中，共有10名患者患有FLT3突变。我们在8例AML 1突变患者中检测到5例（63%）FLT3突变，而在41例AML 1无突变患者中检测到5例（12%）FLT3突变（P = 0.0055）。这些观察结果表明，AML 1活性降低使细胞易于获得活化FLT3突变，作为导致AML M0完全转化的继发事件。
Point mutations of the transcription factor AML1 are associated with leukemogenesis in acute myeloblastic leukemia (AML). Internal tandem duplications (ITDs) in the juxtamembrane domain and mutations in the second tyrosine kinase domain of the Fms-like tyrosine kinase 3 (FLT3) gene represent the most frequent genetic alterations in AML. However, such mutations per se appear to be insufficient for leukemic transformation. To evaluate whether both AML1 and FLT3 mutations contribute to leukemogenesis, we analyzed mutations of these genes in AML M0 subtype in whom AML1 mutations were predominantly observed. Of 51 patients, eight showed a mutation in the Runt domain of the AML1 gene: one heterozygous missense mutation with normal function, five heterozygous frameshift mutations and two biallelic nonsense or frameshift mutations, resulting in haploinsufficiency or complete loss of the AML1 activities. On the other hand, a total of 10 of 49 patients examined had the FLT3 mutation. We detected the FLT3 mutation in five of eight (63%) patients with AML1 mutation, whereas five of 41 (12%) without AML1 mutation showed the FLT3 mutation ( P = 0.0055). These observations suggest that reduced AML1 activities predispose cells to the acquisition of the activating FLT3 mutation as a secondary event leading to full transformation in AML M0.