| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2006: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2005: ¥2,600,000 (Direct Cost: ¥2,600,000)
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| Research Abstract |
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.
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