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

Abstract

Key Points• In AML1-ETO-positive AML cells, HDAC inhibitors induce autophagy, which acts as a prosurvival signal to limit HDAC-induced cell death.• In contrast to the fusion oncoproteins PML-RARA and breakpoint cluster regionabelson, 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 prosurvival response to therapy, thereby reducing treatment efficiency. On the other hand, autophagy may contribute to degradation of fusion oncoproteins, as recently demonstrated for promyelocytic leukemia-retinoic acid receptor a and breakpoint cluster region-abelson, 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-eight-twenty-one (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 prosurvival 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 (CQ) 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. Because VPA and CQ are well-tolerated drugs, combinatorial therapy with VPA and CQ could represent an attractive treatment option for AML1-ETO-positive leukemia. (Blood. 2013;122(14):2467-2476) IntroductionMacroautophagy, hereafter referred to as autophagy, is a catabolic pathway that is upregulated during times of nutrient limitations or stress to maintain cellular metabolism and organelle integrity. 1Autophagy involves sequestration of cytoplasmic cargo, such as long-lived proteins, damaged organelles, and protein aggregates, into double-membrane vesicles termed autophagosomes, which fuse with lysosomes, leading to degradation of the contents by acidic hydrolases. 1 There is currently a pressing need to understand in which settings autophagy should be inhibited and in which instances autophagy should be activated, to overcome drug resistance and optimize cancer treatment. Recent studies indicate that anticancer treatment may be hampered by the activation of autophagy as a prosurvival mechanism that prevents apoptosis and delays necrosis in the cancer cells. 2,3 Thus, including autophagy inhibitors in cancer therapy could potentially overcome cancer drug resistance. 4,5 However, autophagy has also been suggested to be a mediator of cell death in certain contexts, 6 and it was recently demonstrated that autophagy facilitates basal and therapy-induced degradation of promyelocytic leukemia-retinoic acid receptor a (P...

Combined autophagy and HDAC inhibition

“…We and others have demonstrated that inhibition of autophagy leads to synergistic enhancement of the anticancer activity of HDAC inhibitors. 8,9,15,16,[19][20][21] These studies provided the foundation for the clinical evaluation of the autophagy inhibitor HCQ in combination with VOR as a potential novel therapy for advanced solid tumors. We selected 400 mg daily dosing for VOR in this study, which is frequently used for VOR administration.…”

Proteasome inhibitors induce FLT3-ITD degradation through autophagy in AML cells

“…13 For instance, in myeloid leukemia, autophagy induced by arsenic trioxide or all-trans retinoic acid contributes to cell death through the degradation of fusion oncoproteins such as promyelocytic leukemia-retinoic acid receptor alpha (PML-RARA) in acute promyelocytic leukemia cells or breakpoint cluster region-Abelson (BCR-ABL) in chronic myelocytic leukemia cells, whereas it does not mediate degradation of AML1-ETO (another oncoprotein involved in AML), and protects AML1-ETO AML cells from cell death induced by histone deacetylase inhibitors. [31][32][33][34] Thus, elucidating the role of autophagy in genetically defined AML subtypes is critical before exploiting autophagic properties as therapeutic approaches. 13 In addition to PML-RARA and BCR-ABL, our study shows that FLT3-ITD represents another leukemogenic protein targeted by autophagy.…”

A Bim-targeting strategy overcomes adaptive bortezomib resistance in myeloma through a novel link between autophagy and apoptosis

“…24 Notably, HDACIs also modulate autophagy. [25][26][27][28] Currently, the role of Bim in resistance to proteasome inhibitors such as bortezomib is largely unknown. Here we report that Bim is widely expressed in MM cells, and although basal Bim levels do not correlate with intrinsic bortezomib resistance, Bim downregulation confers adaptive bortezomib resistance in Bim hi MM cells.…”