論文 - 詳細
| RRC ID | 56700 |
|---|---|
| 著者 | Tamura M, Yonezawa T, Liu X, Asada S, Hayashi Y, Fukuyama T, Tanaka Y, Kitamura T, Goyama S. |
| タイトル | Opposing effects of acute versus chronic inhibition of p53 on decitabine's efficacy in myeloid neoplasms. |
| ジャーナル | Sci Rep |
| Abstract |
Decitabine is a DNA methyltransferase inhibitor and is considered a promising drug to treat myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) with p53 mutations. However, whether loss of p53 in fact increases the response of MDS/AML cells to decitabine remains unclear. In this study, we assessed the role of p53 in MDS and AML cells treated with decitabine using mouse models for MLL-AF9-driven AML and mutant ASXL1-driven MDS/AML. CRISPR/Cas9-mediated depletion of p53 in MDS/AML cells did not increase, but rather decreased their sensitivity to decitabine. Forced expression of a dominant-negative p53 fragment (p53DD) in these cells also decreased their responses to decitabine, confirming that acute inhibition of p53 conferred resistance to decitabine in AML and MDS/AML cells. In contrast, MLL-AF9-expressing AML cells generated from bone marrow progenitors of Trp53-deficient mice were more sensitive to decitabine in vivo than their wild-type counterparts, suggesting that long-term chronic p53 deficiency increases decitabine sensitivity in AML cells. Taken together, these data revealed a multifaceted role for p53 to regulate responses of myeloid neoplasms to decitabine treatment. |
| 巻・号 | 9(1) |
| ページ | 8171 |
| 公開日 | 2019-6-3 |
| DOI | 10.1038/s41598-019-44496-6 |
| PII | 10.1038/s41598-019-44496-6 |
| PMID | 31160638 |
| PMC | PMC6547685 |
| MeSH | Animals CRISPR-Cas Systems / genetics Cell Line, Tumor Decitabine / pharmacology Disease Models, Animal Gene Expression Regulation, Neoplastic / drug effects Humans Leukemia, Myeloid, Acute / drug therapy* Leukemia, Myeloid, Acute / genetics Leukemia, Myeloid, Acute / pathology Methyltransferases / antagonists & inhibitors* Methyltransferases / genetics Mice Myelodysplastic Syndromes / drug therapy* Myelodysplastic Syndromes / genetics Myelodysplastic Syndromes / pathology Repressor Proteins / genetics Tumor Suppressor Protein p53 / genetics* |
| IF | 4.011 |
| 引用数 | 0 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 1 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| 実験動物マウス | RBRC01361 |