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

Autor: Melanie, Kahl, Annamaria, Brioli, Martin, Bens, Florian, Perner, Anne, Kresinsky, Ulf, Schnetzke, Anna, Hinze, Yordan, Sbirkov, Sven, Stengel, Giorgia, Simonetti, Giovanni, Martinelli, Kevin, Petrie, Arthur, Zelent, Frank-Dietmar, Böhmer, Marco, Groth, Thomas, Ernst, Florian H, Heidel, Sebastian, Scholl, Andreas, Hochhaus, Tino, Schenk
Rok vydání: 2019
Předmět:
Zdroj: Leukemia. 33(11)
ISSN: 1476-5551
Popis: 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.
Databáze: OpenAIRE
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