2007 Fiscal Year Final Research Report Summary
A novel therapy targeting Notch molecule against leukemia and a method to select patients suitable for the therapy
| Project/Area Number |
18590522
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Laboratory medicine
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
SHUJI Tohda Tokyo Medical and Dental University, Department of Laboratory Medicine, Associate Professor (80251510)
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| Project Period (FY) |
2006 – 2007
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| Keywords | Notch / Leukemia / Molecular-targeting therapy / Gamma-secretase / Lymphoma / Myelodysplastic syndrome |
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| Research Abstract |
We previously reported that Notch signaling affected the growth of leukemia cells. Therefore, the regulation of the signaling can be a novel molecular-targeting therapy against leukemia. In this study, we examined molecular mechanism of Notch signaling in the growth of leukemia cells. We also examined the effects of Notch signal inhibitors on the growth.
We examined the effects of gamma-secretase inhibitors on the growth of cell lines derived from acute myeloid leukemia (AML), T-lymphoblastic leukemia (T-ALL), and B-cell lymphoma. We found that gamma-secretase inhibitors suppressed the growth of some cell lines, inducing apoptosis (Oncology Reports 2007). We have established a novel cell line derived from diffuse large B-cell lymphoma. This cell line showed constitutive activation of Notch signaling although it has no mutations in NOTCH1 gene. Gamma-secretase inhibitors suppressed the growth, inducing apoptosis (Leukemia Research 2006).
We have analyzed the mutations in NOTCH1 gene in 20 AML samples and found a missence mutation in PEST domain in one AML case. This case showed constitutive activation of Notch1 protein. We found that NOTCH1 mutations are rare in AML, while more than half of T-ALL have NOTCH1 mutations (Leukemia Lymphoma 2006). We also reported that NOTCH1 mutations was not observed in 20 MDS cases examined. Stimulation with Notch ligand protein slightly suppressed the colony formation (Leukemia Research 2007).
Taken together, we have shown that regulation of Notch signaling can be a molecular-targeting therapy against hematological malignancies such as leukemia.
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