Opposing effects of acute versus chronic inhibition of p53 on decitabine's efficacy in myeloid neoplasms

  • Sci Rep. 2019 Jun 3;9(1):8171. doi: 10.1038/s41598-019-44496-6.
Moe Tamura  1 ,  Taishi Yonezawa  1 ,  Xiaoxiao Liu  1 ,  Shuhei Asada  1 ,  Yasutaka Hayashi  1 ,  Tomofusa Fukuyama  1 ,  Yosuke Tanaka  1 ,  Toshio Kitamura  1 ,  Susumu Goyama  2
Affiliations
  • 1. Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, 108-8639, Tokyo, Japan.
  • 2. Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, 108-8639, Tokyo, Japan. [email protected].
PMID: 31160638 DOI: 10.1038/s41598-019-44496-6
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.

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