The acetyltransferase GCN5 maintains ATRA-resistance in non-APL AML.

Giovanni Martinelli, Tino Schenk, Andreas Hochhaus, Sebastian Scholl, Florian H Heidel, Thomas Ernst, Marco Groth, Frank-Dietmar Böhmer, Arthur Zelent, Kevin Petrie, Melanie Kahl, Giorgia Simonetti, Sven Stengel, Yordan Sbirkov, Anna Hinze, Ulf Schnetzke, Anne Kresinsky, Florian Perner, Martin Bens, Annamaria Brioli

Journal: Leukemia 2020;33(11):2628-2639

PMID: 31576004

Full Text on Nature Publishing Group View on PubMed

Abstract

To date, only one subtype of acute myeloid leukemia (AML), acute promyelocytic leukemia (APL) can be effectively treated by differentiation therapy utilizing all-trans retinoic acid (ATRA). Non-APL AMLs are resistant to ATRA. Here we demonstrate that the acetyltransferase GCN5 contributes to ATRA resistance in non-APL AML via aberrant acetylation of histone 3 lysine 9 (H3K9ac) residues maintaining the expression of stemness and leukemia associated genes. We show that inhibition of GCN5 unlocks an ATRA-driven therapeutic response. This response is potentiated by coinhibition of the lysine demethylase LSD1, leading to differentiation in most non-APL AML. Induction of differentiation was not correlated to a specific AML subtype, cytogenetic, or mutational status. Our study shows a previously uncharacterized role of GCN5 in maintaining the immature state of leukemic blasts and identifies GCN5 as a therapeutic target in AML. The high efficacy of the combined epigenetic treatment with GCN5 and LSD1 inhibitors may enable the use of ATRA for differentiation therapy of non-APL AML. Furthermore, it supports a strategy of combined targeting of epigenetic factors to improve treatment, a concept potentially applicable for a broad range of malignancies.

Address: Department of Hematology/Oncology, Clinic of Internal Medicine II, Jena University Hospital, Jena, Germany.; Institute of Molecular Cell Biology, Center for Molecular Biomedicine Jena (CMB), Jena University Hospital, Jena, Germany.; Else-Kröner-Forschungskolleg, Jena, Germany.; Leibniz-Institute on Aging, Fritz-Lipmann-Institute, Jena, Germany.; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.; Department of Medical Biology, Medical University-Plovdiv, Plovdiv, Bulgaria.; Department of Internal Medicine IV, Jena University Hospital, Jena, Germany.; Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.; Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.; School of Natural Sciences, University of Stirling, Stirling, UK.; Millitary Institute of Hygiene and Epidemiology, Warsaw, Poland.; Department of Hematology/Oncology, Clinic of Internal Medicine II, Jena University Hospital, Jena, Germany. [email protected].; Institute of Molecular Cell Biology, Center for Molecular Biomedicine Jena (CMB), Jena University Hospital, Jena, Germany. [email protected].

DOI: 10.1038/s41375-019-0581-y