Kahl, Melanie, Brioli, Annamaria, Bens, Martin, Perner, Florian, Kresinsky, Anne, Schnetzke, Ulf, Hinze, Anna, Sbirkov, Yordan, Stengel, Sven, Simonetti, Giorgia, Martinelli, Giovanni, Petrie, Kevin, Zelent, Arthur, Böhmer, Frank-Dietmar, Groth, Marco, Ernst, Thomas, Heidel, Florian H, Scholl, Sebastian, Hochhaus, Andreas and Schenk, Tino (2019) The acetyltransferase GCN5 maintains ATRA-resistance in non-APL AML. Leukemia, 33 (11). pp. 2628-2639. ISSN 1476-5551

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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.

Item Type:	Article
Subjects:	Sciences > Biomedical Sciences Sciences > Health Sciences
Divisions:	Faculty of Health Sciences and Wellbeing > School of Medicine
Depositing User:	Kevin Petrie
Date Deposited:	18 Aug 2020 19:25
Last Modified:	04 Sep 2020 13:32
URI:	http://sure.sunderland.ac.uk/id/eprint/12450

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