2020 Fiscal Year Final Research Report
Identification of molecular mechanisms of neutrophil elastase in relapsed/refractory acute myeloid leukemia for developing novel therapies
| Project/Area Number |
19K23912
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| Research Category |
Grant-in-Aid for Research Activity Start-up
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| Allocation Type | Multi-year Fund |
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| Review Section |
0901:Oncology and related fields
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| Research Institution | Nagoya University |
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Principal Investigator |
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| Project Period (FY) |
2019-08-30 – 2021-03-31
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| Keywords | 急性骨髄性白血病 / CBF-AML / 好中球エラスターゼ / セリンプロテアーゼ / PRTN3 |
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| Outline of Final Research Achievements |
We identified the overexpression of PRTN3 gene encoding one of serin proteases in bone marrow specimens from patients with core-binding factor acute myeloid leukemia (CBF-AML) or NRAS mutated non-CBF-AML. We analyzed the molecular biology and significance of PRTN3 in the proliferation and maintenance of AML cells by knocking down of PRTN3 using lentivirally transduced shRNA. When PRTN3 gene was knocked down, AML cell lines showed cell cycle arrest and were induced to apoptosis. Transcriptome analysis revealed the association between the regulation of Ras protein signal transduction and PRTN3 expression in AML. Furthermore, down regulation of PRTN3 showed improved survival in MLL-AF9 AML mice model. These results show its possibility to be a novel target of therapies for AML.
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| Free Research Field |
血液内科
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| Academic Significance and Societal Importance of the Research Achievements |
CBF-AMLはAMLの中でも予後良好群とされるが、現行の治療法では約40%の患者が再発を来す現状は克服すべき課題である。CBF-AMLは染色体異常から生じるキメラ融合分子が白血病発症に関わると報告されているが、その発症、治療抵抗性獲得機序については十分明らかでなく、その解明とともに新規治療法の確立が望まれる。
本研究では、難治性CBF-AML患者検体から新規に同定したセリンプロテアーゼ遺伝子PRTN3の機能解析により、AMLの維持・増殖に関わる既報にない機序が示唆された。この成果から、同分子が新規のAML治療標的として今後治療法開発につながる可能性があり、臨床的観点からも大きな意義がある。
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