| Project/Area Number |
16590446
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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 |
TOHDA Shuji Tokyo Medical and Dental University, Department of Laboratory Medicine, Associate Professor, 大学院・医歯学総合研究科, 助教授 (80251510)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥1,900,000 (Direct Cost: ¥1,900,000)
Fiscal Year 2005: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2004: ¥1,100,000 (Direct Cost: ¥1,100,000)
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| Keywords | Notch / leukemia / Jagged / Delta |
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| Research Abstract |
Notch signaling regulates the self-renewal and differentiation of hematopoietic progenitors. Since acute myeloblastic leukemia (AML) originates from dysregulated hematopoietic progenitors, the Notch system may be involved in the abnormal growth. We previously reported that AML cells express Notch proteins. In this study, we examined the effects of Notch ligands on the growth and differentiation of primary AML cells. AML cells were cultured in wells coated with the ligands or control IgG. The short-term growth, self-renewal capacity and differentiation were evaluated. The ligand stimulation caused three types of response in the short-term growth, namely, promotion, suppression or no significant effect. The self-renewal capacity was suppressed or not significantly affected by the ligands. The ligand stimulation altered blast cells into macrophage-like cells in some samples. Thus, Notch activation caused by the ligand stimulation had diverse effects. The relationship between responsiveness of the cells and prognosis of the patients could not be clarified yet.
Effects of Notch activation on retinoic acid (RA)-induced differentiation and apoptosis were investigated. Acute promyelocytic leukemia (APL) cells undergo neutrophilic differentiation and apoptosis by RA. Notch activation induced by the Notch ligands made part of RA-treated NB4 cells monocyte-like shaped and reduced the apoptosis. The ligands suppressed the RA-induced cleavage of caspase-8 and PARP, which may be a possible mechanism through which the ligands suppress the RA-induced apoptosis.
The effect of the Notch ligands on drug-sensitivity of leukemia cells was examined. The drug-induced growth suppression was slightly reduced by the ligand stimulation in some cells. The ligand-coated culture-plates are more similar to the microenvironment in human bone marrow than ordinary plates. We will further examine the clinical usefulness of the drug-sensitivity test using the ligand-coated plates.
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