Open AccessOpposing effects of acute versus chronic inhibition of p53 on decitabine’s efficacy in myeloid neoplasms
Author(s) -
Moe Tamura,
Taishi Yonezawa,
Xiaoxiao Liu,
Shuhei Asada,
Yasutaka Hayashi,
Tsutomu Fükuyama,
Yosuke Tanaka,
Toshio Kitamura,
Susumu Goyama
Publication year - 2019
Publication title -
scientific reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.24
H-Index - 213
ISSN - 2045-2322
DOI - 10.1038/s41598-019-44496-6
Subject(s) - decitabine , myeloid leukemia , azacitidine , myelodysplastic syndromes , cancer research , medicine , myeloid , progenitor cell , chronic myelomonocytic leukemia , bone marrow , leukemia , immunology , biology , dna methylation , stem cell , gene expression , gene , genetics
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.