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

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)2628-2639
Number of pages12
JournalLeukemia
Volume33
Issue number11
DOIs
Publication statusPublished - Nov 1 2019

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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