Open AccessSynergistic effects of PRIMA-1Met (APR-246) and 5-azacitidine in TP53-mutated myelodysplastic syndromes and acute myeloid leukemia
Author(s) -
Nabih Maslah,
Norman Salomao,
Louis Drevon,
Emmanuelle Verger,
Nicolas Partouche,
Pierre Ly,
Philippe Aubin,
Nadia Naoui,
MarieHélène Schlageter,
Cécile Bally,
Elsa Miekoutima,
Ramy Rahmé,
Jacqueline Lehmann-Che,
Lionel Adès,
Pierre Fenaux,
Bruno Cassinat,
Stéphane Giraudier
Publication year - 2019
Publication title -
haematologica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.782
H-Index - 142
eISSN - 1592-8721
pISSN - 0390-6078
DOI - 10.3324/haematol.2019.218453
Subject(s) - azacitidine , myelodysplastic syndromes , myeloid leukemia , cancer research , leukemia , apoptosis , myeloid , transactivation , decitabine , medicine , immunology , biology , bone marrow , gene , dna methylation , gene expression , genetics
Myelodysplastic syndromes and acute myeloid leukemia with TP53 mutations are characterized by frequent relapses, poor or short responses, and poor survival with the currently available therapies including chemotherapy and 5-azacitidine (AZA). PRIMA-1 Met (APR-246,APR) is a methylated derivative of PRIMA-1, which induces apoptosis in human tumor cells through restoration of the transcriptional transactivation function of mutant p53. Here we show that low doses of APR on its own or in combination with AZA reactivate the p53 pathway and induce an apoptosis program. Functionally, we demonstrate that APR exerts these activities on its own and that it synergizes with AZA in TP53 -mutated myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML) cell lines and in TP53 -mutated primary cells from MDS/AML patients. Low doses of APR on its own or in combination with AZA also show significant efficacy in vivo Lastly, using transcriptomic analysis, we found that the APR + AZA synergy was mediated by downregulation of the FLT3 pathway in drug-treated cells. Activation of the FLT3 pathway by FLT3 ligand reversed the inhibition of cell proliferation by APR + AZA. These data suggest that TP53 -mutated MDS/AML may be better targeted by the addition of APR-246 to conventional treatments.