Hyperactivation of the RAS signaling pathway in myelodysplastic syndrome with AML1/RUNX1 point mutations
Hyperactivation of the RAS signaling pathway in myelodysplastic syndrome with AML1/RUNX1 point mutations
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DOI：
10.1038/sj.leu.2404136
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发表时间：
2006-04-01
期刊：
影响因子：
11.4
通讯作者：
Kimura, A
中科院分区：
文献类型：
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作者：
Niimi, H;Harada, H;Kimura, A
AML1/RUNX1 突变在骨髓增生异常综合征 (MDS) 患者中经常被报道，尤其是那些诊断为难治性贫血伴原始细胞过多 (RAEB)、RAEB 转化 (RAEBt) 或 MDS 后 AML 的患者（这些类别被定义为 MDS/AML）。尽管 AML1 突变被怀疑在 MDS/AML 的发展中发挥着关键作用，但获得额外的基因改变也是必要的。我们分析了具有 AML1 突变的 MDS/AML 患者的基因改变，并将其与没有 AML1 突变的患者的基因改变进行比较。 AML1突变与-7/7q-显着相关，而没有AML1突变的MDS/AML患者则表现出高频率的-5/5q-和复杂的核型。 AML1突变患者的FLT3、N-RAS、PTPN11和NF1基因突变较多，导致AML1突变MDS/AML患者的受体酪氨酸激酶（RTK）-RAS信号通路突变频率显着高于AML1野生型MDS/AML患者（38% vs 6.3%，P < 0.0001）。相反，p53 突变仅在没有 AML1 突变的患者中检测到。此外，表达表面c-KIT和SHP-2突变体的AML1突变患者的母细胞在干细胞因子刺激后有助于延长和增强细胞外信号调节激酶的激活。我们的结果表明，由 AML1/RUNX1 突变引起的 MDS/AML 与 -7/7q- 改变显着相关，并且经常涉及 RTK-RAS 信号通路激活。
AML1/RUNX1 mutations have been reported frequently in myelodysplastic syndrome (MDS) patients, especially those diagnosed with refractory anemia with excess blast (RAEB), RAEB in transformation (RAEBt), or AML following MDS (these categories are defined as MDS/AML). Although AML1 mutations are suspected to play a pivotal role in the development of MDS/AML, acquisition of additional genetic alterations is also necessary. We analyzed gene alterations in MDS/AML patients with AML1 mutations, comparing them to alterations in those without an AML1 mutation. AML1 mutations were significantly associated with -7/7q-, whereas MDS/AML patients without AML1 mutations showed a high frequency of -5/5q- and a complex karyotype. Patients with AML1 mutations showed more mutations of their FLT3, N-RAS, PTPN11, and NF1 genes, resulting in a significantly higher mutation frequency for receptor tyrosine kinase (RTK)-RAS signaling pathways in AML1-mutated MDS/AML patients compared to AML1-wild-type MDS/AML patients (38% versus 6.3%, P < 0.0001). Conversely, p53 mutations were detected only in patients without AML1 mutations. Furthermore, blast cells of the AML1-mutated patients expressing surface c-KIT, and SHP-2 mutants contributed to prolonged and enhanced extracellular signal-regulated kinase activation following stem cell factor stimulation. Our results suggest that MDS/AML arising from AML1/RUNX1 mutations has a significant association with -7/7q- alteration, and frequently involves RTK-RAS signaling pathway activation.