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

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

Item Type: Article


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.

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Depositing User: Kevin Petrie


Item ID: 12450
Identification Number:
ISSN: 1476-5551
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Users with ORCIDS

ORCID for Kevin Petrie: ORCID iD

Catalogue record

Date Deposited: 18 Aug 2020 19:25
Last Modified: 04 Sep 2020 13:32


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

University Divisions

Faculty of Health Sciences and Wellbeing > School of Medicine


Sciences > Biomedical Sciences
Sciences > Health Sciences

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