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

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