| Project/Area Number |
19K08847
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 54010:Hematology and medical oncology-related
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| Research Institution | Jichi Medical University |
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Principal Investigator |
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | 慢性骨髄性白血病 / オートファジー / AMPK / ｍTOR / p53 / mTOR / BCR-ABL |
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| Outline of Research at the Start |
慢性骨髄性白血病の原因遺伝子であるBCR-ABLの細胞内における局在制御のメカニズムを解明し、新規治療法の開発に繋げていく。
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| Outline of Final Research Achievements |
Chronic myeloid leukemia (CML) is driven by the BCR-ABL oncoprotein, a constitutively active protein tyrosine kinase. Although tyrosine kinase inhibitors (TKIs) have greatly improved the prognosis of CML patients, the emergence of TKI resistance is an important clinical problem, which deserves additional treatment options based on unique biological properties to CML cells. The BCR-ABL protein activates AMP-activated protein kinase (AMPK) for ATP production and the mechanistic target of rapamycin (mTOR) pathway to suppress autophagy. BCR-ABL is detected in the nuclei of advanced-stage CML cells, in which ATP is sufficiently supplied via enhanced glucose metabolism. AMPK is hyperactivated under energy-deprived conditions and triggers autophagy via ULK1 phosphorylation and mTOR inhibition. This pathway represents a novel therapeutic vulnerability that may be useful for treating TKI-resistant CML.
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| Academic Significance and Societal Importance of the Research Achievements |
CML患者は寛解を維持するためにはTKIを長期内服せざるを得ない。本研究成果により、急性期CMLではBCR-ABLの細胞内局在の異常がTKI抵抗性に寄与していると考えられた。今後、急性期CML症例やTKI抵抗性症例においての治療戦略を考える上で重要な研究成果と考えられる。
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