Targeting chemoresistance and mitochondria-dependent metabolic reprogramming in acute myeloid leukemia

Abstract

Chemoresistance often complicates the management of cancer, as noted in the instance of acute myeloid leukemia (AML). Mitochondrial function is considered important for the viability of AML blasts and appears to also modulate chemoresistance. As mitochondrial metabolism is aberrant in AML, any distinct pathways could be directly targeted to impact both cell viability and chemoresistance. Therefore, identifying and targeting those precise rogue elements of mitochondrial metabolism could be a valid therapeutic strategy in leukemia. Here, we review the evidence for abnormalities in mitochondria metabolic processes in AML cells, that likely impact chemoresistance. We further address several therapeutic approaches targeting isocitrate dehydrogenase 2 (IDH2), CD39, nicotinamide phosphoribosyl transferase (NAMPT), electron transport chain (ETC) complex in AML and also consider the roles of mesenchymal stromal cells. We propose the term "mitotherapy" to collectively refer to such regimens that attempt to override mitochondria-mediated metabolic reprogramming, as used by cancer cells. Mounting evidence suggests that mitotherapy could provide a complementary strategy to overcome chemoresistance in liquid cancers, as well as in solid tumors.

Keywords: acute myeloid leukemia; chemoresistance; metabolic reprogramming; mitochondrial metabolism; mitotherapy.

Figure 1

The mitochondrial bioenergetic signature of AML cells. ATP, adenosine triphosphate; Cyt c, cytochrome c; mtDNA, mitochondrial DNA; NAD⁺, nicotinamide adenine dinucleotide; OXPHOS, oxidative phosphorylation; Q, coenzyme Q; TCA cycle, tricarboxylic acid cycle.

Figure 2

Emerging mitochondrial-targeted treatments or “mitotherapies” directed at aberrant intrinsic mitochondria metabolic processes in AML. (A) The accumulation of intracellular (R)-2-HG, catalyzed by mutant IDH1 and IDH2, increases DNA and histone methylation, associating with chemoresistance in AML. (B) CD39 promotes mitochondrial biogenesis and drives OXPHOS via ATF4 and a P2RY13-cAMP/PKA signaling, resulting in the intrinsic chemoresistance in AML cells. (C) NAD⁺ drives OXPHOS by activating the NAD⁺-dependent catabolism of amino acids and fatty acids. NAMPT inhibitors decrease mitochondrial activity and increases apoptosis in AML cells. (D) Inhibitions of OXPHOS cause altered oxygen consumption rates and decreased ATP production and have synergistic effects with anti-leukemia therapeutics. ADP, adenosine diphosphate; ATP, adenosine triphosphate; Cyt c, cytochrome c; IDH, isocitrate dehydrogenase; IDHi, inhibitors to IDH-mutant proteins; mut, mutant; NAD⁺, nicotinamide adenine dinucleotide; NAMPT, nicotinamide phosphoribosyl transferase; OXPHOS, oxidative phosphorylation; Q, coenzyme Q; (R)-2-HG, (R)-2-hydroxyglutarate; TCA cycle, tricarboxylic acid cycle.

Figure 3

Mitochondria trafficking from MSCs to AML and related therapies to overcome chemoresistance (1). MSCs transfer their mitochondrial cargo to AML cells via various mechanisms, including TNTs, GJCs, extracellular vesicles, and cell fusion (2). Mitochondria trafficking can be further boosted by chemotherapy. Increased mitochondria contribute to high ROS levels in AML, which in turn promotes mitochondria trafficking from MSCs as a positive feedback mechanism (3). In AML, high ROS drives genomic instability, leading to chemotherapy resistance. MSCs stimulate the expression of UCP2 in leukemic cells, which suppresses the import of pyruvate into mitochondria, inducing a “Warburg phenotype”, and reduces the production of ROS, engendering AML cells to be in a quiescent state and resistant to chemotherapy. α-KG, α-ketoglutarate; AML, Acute myeloid leukemia; BCL-2, B-cell lymphoma 2; Cx43, Connexin 43; G6P, glucose 6-phosphate; GJCs, gap-junction channels; HK2, hexokinase 2; MPC, mitochondrial pyruvate carrier; MSC, mesenchymal stromal cell; mtDNA, mitochondrial DNA; NOX2, nicotinamide adenine dinucleotide phosphate oxidases 2; OXPHOS, oxidative phosphorylation; ROS, reactive oxygen species; TCA cycle, tricarboxylic acid cycle; TNTs, tunnelling nanotubes; UCP2, uncoupling protein 2.