The role of autophagy in targeted therapy for acute myeloid leukemia

Abstract

Although molecular targeted therapies have recently displayed therapeutic effects in acute myeloid leukemia (AML), limited response and acquired resistance remain common problems. Numerous studies have associated autophagy, an essential degradation process involved in the cellular response to stress, with the development and therapeutic response of cancers including AML. Thus, we review studies on the role of autophagy in AML development and summarize the linkage between autophagy and several recurrent genetic abnormalities in AML, highlighting the potential of capitalizing on autophagy modulation in targeted therapy for AML.Abbreviations: AML: acute myeloid leukemia; AMPK: AMP-activated protein kinase; APL: acute promyelocytic leukemia; ATG: autophagy related; ATM: ATM serine/threonine kinase; ATO: arsenic trioxide; ATRA: all trans retinoic acid; BCL2: BCL2 apoptosis regulator; BECN1: beclin 1; BET proteins, bromodomain and extra-terminal domain family; CMA: chaperone-mediated autophagy; CQ: chloroquine; DNMT, DNA methyltransferase; DOT1L: DOT1 like histone lysine methyltransferase; FLT3: fms related receptor tyrosine kinase 3; FIS1: fission, mitochondrial 1; HCQ: hydroxychloroquine; HSC: hematopoietic stem cell; IDH: isocitrate dehydrogenase; ITD: internal tandem duplication; KMT2A/MLL: lysine methyltransferase 2A; LSC: leukemia stem cell; MDS: myelodysplastic syndromes; MTORC1: mechanistic target of rapamycin kinase complex 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; NPM1: nucleophosmin 1; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PML: PML nuclear body scaffold; ROS: reactive oxygen species; RB1CC1/FIP200: RB1 inducible coiled-coil 1; SAHA: vorinostat; SQSTM1: sequestosome 1; TET2: tet methylcytosine dioxygenase 2; TKD: tyrosine kinase domain; TKI: tyrosine kinase inhibitor; TP53/p53: tumor protein p53; ULK1: unc-51 like autophagy activating kinase 1; VPA: valproic acid; WDFY3/ALFY: WD repeat and FYVE domain containing 3.

Keywords: Acute myeloid leukemia; autophagy; autophagy modulator; genetic abnormalities; molecular targeted therapy.

Figure 1.

The roles of autophagy in the development and targeted therapy response of AML with FLT3 mutations. FLT3-ITD mutations promote autophagy in AML cells via ATF4, which benefits leukemia cell survival and acquired resistance to FLT3 inhibitors. Coupling FLT3-inhibiting agents with autophagy inhibitors enhances the therapeutic effectiveness for FLT3-mutated AML. Proteasome inhibitors and RET suppression (RET inhibits autophagy by activating MTORC1) can stimulate mutated-FLT3 degradation by enhancing autophagy activity, holding promise as a combinatorial treatment for FLT3-mutated AML

Figure 2.

The interactions of autophagy with NPM1-mutated (mt-NPM1) AML. NPM1 interacts with PML in the nucleus. Mutated NPM1 abnormally localizes at the cytoplasm, leading to PML cytoplasmic delocalization and stabilization. Aberrantly-accumulated PML enhances autophagy levels via AKT and promotes leukemic cell survival and the progression of AML with NPM1 mutations. Pharmacological repression of autophagy and/or PML may be a promising approach for treating NPM1-mutated AML patients

Figure 3.

The associations between autophagy with AML depending on TP53 status. (A) for AML with wild-type TP53, autophagy suppression activates TP53 to increase the efficacy of promoting apoptosis. (B) for AML with TP53 mutations (mt-TP53), HSP90 inhibitor 17-AAG induces macroautophagy to promote the autophagic degradation of TP53^R248Q. When metabolic stress suppresses macroautophagy, 17-AAG can mediate the CMA-dependent degradation of TP53^R248Q in AML cells. (C) for AML with wild-type TP53 under cellular stresses, activated TP53 by cellular stress promotes autophagy induction to induce cell death

Figure 4.

The role of autophagy in epigenetic dysregulation in AML. (A) HDAC inhibitors repress autophagic flux in DS-AMKL cells exhibiting low basal autophagy levels because of MTORC1 activation, contributing to apoptotic effects of HDAC inhibition. In contrast, t(8:21) AML cells acquire resistance against HDAC inhibitors due to autophagy induction, and the combination of HDAC inhibitors with pharmacological autophagy suppression represents a promising approach to overcoming resistance of t(8:21) AML. (B) BET inhibitors enhance autophagy through the activation of the AMPK-ULK1 pathway, thus conferring drug resistance to leukemia stem cells, which can be overcome by synergistic treatment with AMPK-inhibiting agents

Figure 5.

Interactions between autophagy and fusion oncoproteins caused by chromosome rearrangements in AML. (A) The differentiation-inducing agent ATRA can enhance autophagy through MTORC1 repression, and stimulated autophagy activity promotes PML-RARA autophagic degradation via a variety of mechanisms. (B) The stability of KMT2A-MLLT3 and KMT2A-AFF1 fusion proteins is maintained by LAMP5 through the suppression of selective autophagic degradation, and DOT1L mediates the activation of LAMP5. LAMP5 knockdown can be applied to synergize with DOT1L inhibitors to promote KMT2A fusion eradication for KMT2A treatment