Opposing effects of acute versus chronic inhibition of p53 on decitabine\u2019s efficacy in myeloid neoplasms

Moe Tamura,Shuhei Asada,Xiaoxiao Liu,Taishi Yonezawa,Toshio Kitamura,Yosuke Tanaka,Susumu Goyama,Yasutaka Hayashi,Tomofusa Fukuyama

doi:10.1038/s41598-019-44496-6

Moe Tamura, Shuhei Asada + Show 7 more

Open Access

https://doi.org/10.1038/s41598-019-44496-6

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Journal: Scientific Reports	Publication Date: Jun 3, 2019
Citations: 12	License type: open-access

Affiliation: The University of Tokyo

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.

Highlights

P53, encoded by TP53 in humans and Trp[53] in mice, is the most frequently mutated gene in human cancer1,2. p53 is a transcription factor and regulates expression of downstream target genes involved in diverse cellular processes, including apoptosis, cell cycle arrest, senescence, and metabolic regulation
Recent clinical studies have shown that patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) who had p53 mutations exhibited favorable responses to the treatment with decitabine[3,4]
Consistent with the clinical observations, experimental studies have shown that decitabine induces cell death preferentially in p53 null or mutated cells than in p53 wild-type cells[7,8,9]. These findings suggest that decitabine is a promising drug to treat MDS and AML with p53 mutations

Summary

Introduction

P53, encoded by TP53 in humans and Trp[53] in mice, is the most frequently mutated gene in human cancer1,2. p53 is a transcription factor and regulates expression of downstream target genes involved in diverse cellular processes, including apoptosis, cell cycle arrest, senescence, and metabolic regulation. Consistent with the clinical observations, experimental studies have shown that decitabine induces cell death preferentially in p53 null or mutated cells than in p53 wild-type cells[7,8,9]. These findings suggest that decitabine is a promising drug to treat MDS and AML with p53 mutations. (f) Shown are FACS profiles of Annexin V and DAPI expression of vehicle- or decitabine-treated MLL-AF9 cells. We have developed several mouse models for AML and MDS with MLL fusions or ASXL1 mutations. We have shown that a C-terminally truncated ASXL1 mutant promotes the development of MDS and AML in concert with NRAS, SETBP1 and RUNX1 mutations[16,18,19,20,21]

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