Targeting autophagy potentiates the apoptotic effect of histone deacetylase inhibitors in t(8;21) AML cells

Maria Lyngaas Torgersen, Nikolai Engedal, Stig-Ove Bøe, Peter Hokland and Anne Simonsen

Key points

  • In AML1-ETO-positive AML cells, HDAC inhibitors induce autophagy, which acts as a pro-survival signal to limit HDAC-induced cell death.

  • In contrast to the fusion oncoproteins PML-RARA and BCR-ABL, AML1-ETO is not degraded by either basal- or drug-induced autophagy.


The role of autophagy during leukemia treatment is unclear. On the one hand, autophagy might be induced as a pro-survival response to therapy, thereby reducing treatment efficiency. On the other hand, autophagy may contribute to degradation of fusion oncoproteins, as recently demonstrated for PML-RARA and BCR-ABL, thereby facilitating leukemia treatment. Here, we investigated these opposing roles of autophagy in t(8;21) acute myeloid leukemia (AML) cells, which express the most frequently occurring AML fusion oncoprotein, AML1-ETO. We demonstrate that autophagy is induced by AML1-ETO-targeting drugs, such as the histone deacetylase inhibitors (HDACis) valproic acid (VPA) and vorinostat. Furthermore, we show that autophagy does not mediate degradation of AML1-ETO, but rather has a pro-survival role in AML cells as inhibition of autophagy significantly reduced the viability and colony-forming ability of HDACi-treated AML cells. Combined treatment with HDACis and autophagy inhibitors such as chloroquine, led to a massive accumulation of ubiquitinated proteins that correlated with increased cell death. Finally, we show that VPA induced autophagy in t(8;21) AML patient cells, and combined treatment with CQ enhanced cell death. Since VPA and chloroquine are well-tolerated drugs, combinatorial therapy with VPA and CQ could represent an attractive treatment option for AML1-ETO positive leukemia.

  • Submitted May 3, 2013.
  • Accepted August 11, 2013.