RRC ID 56700
Author Tamura M, Yonezawa T, Liu X, Asada S, Hayashi Y, Fukuyama T, Tanaka Y, Kitamura T, Goyama S.
Title Opposing effects of acute versus chronic inhibition of p53 on decitabine's efficacy in myeloid neoplasms.
Journal 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.
Volume 9(1)
Pages 8171
Published 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
Times Cited 0
Mice RBRC01361