Genetic pathway in molecular pathogenesis of myelodysplastic syndrome

AML1/RUNX1突变在骨髓增生异常综合征（MDS）患者中经常被报道。虽然AML1突变被怀疑在MDS/AML的发展中起关键作用，但获得额外的遗传改变也是必要的。我们分析了AML1突变的MDS/AML患者的基因改变，并将其与没有AML1突变的患者进行了比较。AML1突变与-7/7q-显著相关，而没有AML1突变的MDS/AML患者表现出高频率的-5/5q和复杂的核型。AML1突变患者的FLT3、N-RAS、PTPN11和NF1基因突变更多，导致AML1突变的MDS/AML患者中受体酪氨酸激酶(RTK)-RAS信号通路的突变频率显著高于AML1野生型MDS/AML患者（38%对6.3%，P< 0.0001）。相反，只有在没有AML1突变的患者中检测到p.53突变。此外，aml1突变患者的胚细胞表达表面c-KIT和SHP-2突变，有助于在SCF刺激后延长和增强ERK激活。我们的研究结果表明，由AML1/RUNX1突变引起的MDS/AML与-7/7q改变有显著关联，并且经常涉及RTK-RAS信号通路的激活。我们使用AML1突变体转导的骨髓细胞进行小鼠骨髓移植。大多数小鼠在移植后几个月内出现MDS/ aml样症状。携带AML1突变的逆转录病毒载体的迁移改变了一些基因的表达模式，这些基因似乎与AML1突变体协同发展MDS/AML。我们也尝试将AML1突变转导到人造血干细胞中，发现其形态改变和增殖异常。现在我们继续这个项目。此外，我们发现CEBPA基因突变是无AML1突变的MDS/AML的主要事件之一。

AML1/RUNX1 mutations have been reported frequently in myelodysplastic syndrome (MDS) patients. 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-wildtype MDS/AML patients (38% versus 6.3%, P<.0001). Conversely, p.53 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 ERK activation following SCF 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.We performed mouse bone marrow transplantation using bone marrow cells transduced with AML1 mutants. Most mice developed MDS/AML-like symptoms within several months after the transplant. The expression patterns of some genes have been changed by immigration of retrovirus vectors harboring AML1-mutations, and these genes seemed to collaborate with AML1 mutants to develop MDS/AML. We also tried to transduce AML1 mutation into human hematopoietic stem cells, and found their morphological changes and abnormal proliferation. Now we continue this project. Furthermore, we found that CEBPA gene mutation is one of the master events to develop MDS/AML without AML1 mutation.