Article

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

Details

Citation

Kahl M, Brioli A, Bens M, Perner F, Kresinsky A, Schnetzke U, Hinze A, Sbirkov Y, Stengel S, Simonetti G, Martinelli G, Petrie K, Zelent A, Bohmer F & Groth M (2019) The acetyltransferase GCN5 maintains ATRA-resistance in non-APL AML. Leukemia, 33 (11), p. 2628–2639. https://doi.org/10.1038/s41375-019-0581-y

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.

Keywords
targeted therapies; translational research

Notes
Additional co-authors: Thomas Ernst, Florian H. Heidel, Sebastian Scholl, Andreas Hochhaus & Tino Schenk

Journal
Leukemia: Volume 33, Issue 11

StatusPublished
FundersGerman Research Foundation
Publication date01/11/2019
Publication date online01/10/2019
Date accepted by journal04/07/2019
ISSN0887-6924
eISSN1476-5551