Page 81 - Haematologica - Vol. 105 n. 6 - June 2020

Myelodysplastic Syndromes
Synergistic effects of PRIMA-1Met (APR-246) and 5-azacitidine in TP53-mutated myelodys- plastic syndromes and acute myeloid leukemia
Nabih Maslah,1,2,3 Norman Salomao,3 Louis Drevon,3 Emmanuelle Verger,1,3 Nicolas Partouche,4 Pierre Ly,1 Philippe Aubin,1 Nadia Naoui,1 Marie-Helene Schlageter,1,3 Cecile Bally,5 Elsa Miekoutima,5 Ramy Rahmé,5 Jacqueline Lehmann-Che,2,6 Lionel Ades,2,3,5 Pierre Fenaux,2,3,5 Bruno Cassinat1,3# and Stephane Giraudier1,2,3#
1APHP, Service de Biologie Cellulaire, Hôpital Saint-Louis, Paris; 2Faculté de Médecine Université Paris Diderot Paris 7, Paris; 3INSERM UMR-S 1131, Hôpital Saint-Louis, Paris; 4Faculté de Médecine Paris 12-UPEC, Hôpital Henri Mondor, APHP, Créteil; 5APHP, Service d'Hématologie Senior, Hôpital Saint-Louis, Paris and 6Unité d’Oncologie Moléculaire, Hôpital Saint-Louis, APHP, Paris, France
#BC and SG contributed equally as co-senior authors
ABSTRACT
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-1Met (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 apop- tosis program. Functionally, we demonstrate that APR exerts these activities on its own and that it synergizes with AZA in TP53-mutated myelodysplas- tic 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.
Introduction
Myelodysplastic syndromes (MDS) are malignant bone marrow disorders charac- terized by ineffective hematopoiesis leading to refractory cytopenias, and by an increased risk of progression to acute myeloid leukemia (AML).1 They are prognos- tically stratified on the basis of the percentage of blasts in the bone marrow, the kary- otype, and the number of cytopenias present according to an International Prognostic Scoring System (IPSS),2 which was recently revised (revised IPSS, IPSS-R).2 Current studies are integrating data on somatic gene mutations into prognostic indices to fur- ther refine risk stratification.3-6 At the genetic level, it is now widely recognized that most of the clinical and pathological features of MDS and AML are the direct result of recurrent acquired somatic genetic lesions. Among these, TP53 gene mutations have been shown to occur in 5-10% of all MDS and AML cases,3-5,7-9 including 20- 25% of the low-risk MDS with isolated del 5q,7 and 40-50% of the MDS and AML with complex karyotypes.8-10 Among MDS with complex karyotypes, the presence of TP53 mutations has been correlated with a lower number of other mutations and a poorer outcome.11 Furthermore, the allelic burden of the TP53 mutations has been
Ferrata Storti Foundation
Haematologica 2020 Volume 105(6):1539-1551
Correspondence:
STEPHANE GIRAUDIER
stephane.giraudier@aphp.fr
Received: February 4, 2019. Accepted: September 4, 2019. Pre-published: September 5, 2019.
doi:10.3324/haematol.2019.218453
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/6/1539
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