| 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
|
| リソース情報 |
| 実験動物マウス |
RBRC01361 |
