| Project/Area Number |
17K09019
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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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| Research Field |
Laboratory medicine
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| Research Institution | Tohoku Medical and Pharmaceutical University |
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Principal Investigator |
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| Project Period (FY) |
2017-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2020: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2019: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | AML / PU.1 / メタロチオネイン（MT） / SIRPa / FLT3 / メタロチオネイン / SIRPα / 癌 / 白血病 / 細胞分化 / 細胞増殖 / バイオマーカー |
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| Outline of Final Research Achievements |
To clarify the mechanisms of AML, we analyzed several PU.1 target genes those we identified (metallothionein [MT], signal regulatory protein alfa, FLT3). We already revealed that the down regulation of PU.1, which results in the development of AML, leads to the up regulation of MT expression and inhibition of myeloid differentiation. In the current study, we revealed that MT does not play a major role in the monocyte development, which is rather contrast to myeloid differentiation. We further demonstrated that over-expression of MT in NB4(acute promyelocytic leukemia) cells resulted in the modest (1.5 fold) increment of the 50% effective dose to the cytarabine, through the suppression of the induction of reactive oxygen species. Moreover, serum stimulation experiments revealed that the proportion of the S-phase cells are increased in the MT over-expressed cells. These suggest that MT is playing a role in the drug resistance and aberrant cell proliferation in PU.1 down-regulated AML.
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| Academic Significance and Societal Importance of the Research Achievements |
PU.1の発現低下がAMLの病態に重要な役割を担っていることは明らかであったが、申請者のグループはPU.1が制御する遺伝子として、メタロチオネイン（MT)、signal regulatory protein alfa、FLT3などを独自に明らかにしている。本研究はそれら分子のAML病態における意義について検討したものである。本期間において、MT過剰発現はAMLの代表的な治療薬であるAra-Cに対して耐性に働くこと、それは活性酸素の産生を抑えることで耐性に関与していることを示した。すなわち、AMLの異常細胞増殖と抗がん剤耐性に関してその機序の一端を明らかにするものである。
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