The Role of Metabolism in the Development of Personalized Therapies in Acute Myeloid Leukemia

Dembitz, Vilma; Gallipoli, Paolo

doi:10.3389/fonc.2021.665291

Cited by 7 publications

(4 citation statements)

References 98 publications

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“…1 mitochondrial functions such as BCL2 family members [23,[28][29][30][31]. Metabolic adaptations in AML have been reported to entail rewiring of carbon and nitrogen fluxes that promote mitochondrial respiration and redox homeostasis [15,[35][36][37][38]. Studies using patient-derived xenograft (PDX) models revealed that araC-resistant AML cells overexpress genes driving OX/PHOS [39,40], whereas murine syngeneic AML models have shown that residual cells increase the uptake of glutamine and aspartate to fuel OX/PHOS and synthesize pyrimidine and glutathione [41], which may represent adaptations required to survive in that context.…”

Section: Introductionmentioning

confidence: 99%

EIF4A inhibition targets bioenergetic homeostasis in AML MOLM-14 cells in vitro and in vivo and synergizes with cytarabine and venetoclax

Fooks

Galicia-Vázquez

Gife

et al. 2022

J Exp Clin Cancer Res

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Background Acute myeloid leukemia (AML) is an aggressive hematological cancer resulting from uncontrolled proliferation of differentiation-blocked myeloid cells. Seventy percent of AML patients are currently not cured with available treatments, highlighting the need of novel therapeutic strategies. A promising target in AML is the mammalian target of rapamycin complex 1 (mTORC1). Clinical inhibition of mTORC1 is limited by its reactivation through compensatory and regulatory feedback loops. Here, we explored a strategy to curtail these drawbacks through inhibition of an important effector of the mTORC1signaling pathway, the eukaryotic initiation factor 4A (eIF4A). Methods We tested the anti-leukemic effect of a potent and specific eIF4A inhibitor (eIF4Ai), CR-1-31-B, in combination with cytosine arabinoside (araC) or the BCL2 inhibitor venetoclax. We utilized the MOLM-14 human AML cell line to model chemoresistant disease both in vitro and in vivo. In eIF4Ai-treated cells, we assessed for changes in survival, apoptotic priming, de novo protein synthesis, targeted intracellular metabolite content, bioenergetic profile, mitochondrial reactive oxygen species (mtROS) and mitochondrial membrane potential (MMP). Results eIF4Ai exhibits anti-leukemia activity in vivo while sparing non-malignant myeloid cells. In vitro, eIF4Ai synergizes with two therapeutic agents in AML, araC and venetoclax. EIF4Ai reduces mitochondrial membrane potential (MMP) and the rate of ATP synthesis from mitochondrial respiration and glycolysis. Furthermore, eIF4i enhanced apoptotic priming while reducing the expression levels of the antiapoptotic factors BCL2, BCL-XL and MCL1. Concomitantly, eIF4Ai decreases intracellular levels of specific metabolic intermediates of the tricarboxylic acid cycle (TCA cycle) and glucose metabolism, while enhancing mtROS. In vitro redox stress contributes to eIF4Ai cytotoxicity, as treatment with a ROS scavenger partially rescued the viability of eIF4A inhibition. Conclusions We discovered that chemoresistant MOLM-14 cells rely on eIF4A-dependent cap translation for survival in vitro and in vivo. EIF4A drives an intrinsic metabolic program sustaining bioenergetic and redox homeostasis and regulates the expression of anti-apoptotic proteins. Overall, our work suggests that eIF4A-dependent cap translation contributes to adaptive processes involved in resistance to relevant therapeutic agents in AML.

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Section: Introductionmentioning

confidence: 99%

EIF4A inhibition targets bioenergetic homeostasis in AML MOLM-14 cells in vitro and in vivo and synergizes with cytarabine and venetoclax

Fooks

Galicia-Vázquez

Gife

et al. 2022

J Exp Clin Cancer Res

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“…Although specific mutations can dictate selective metabolic vulnerabilities( 44 ), metabolic dependencies can be present across multiple genetic backgrounds as a phenotype bottleneck i.e. a state essential for continued tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

SCD inhibition preferentially eradicates AML displaying high de novo fatty acid desaturation and synergizes with chemotherapy

Dembitz

Lawson

Burt

et al. 2023

Preprint

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Identification of specific and therapeutically actionable vulnerabilities in acute myeloid leukaemia (AML) is needed to improve patients’ outcome. These features should be ideally present in many patients independently of mutational background. Here we identifyde novofatty acid (FA) desaturation, specifically stearoyl-CoA desaturase (SCD) inhibition, as a therapeutic vulnerability across multiple AML modelsin vitroandin vivo. SCD inhibition induces AML cell deathviapleiotropic effects, and sensitivity is based on their dependency on FA desaturation regardless of mutational profile. Its efficacy is enhanced by driving FA biosynthesisin vitroand is less prominentin vivodue to stromal protection. SCD inhibition increases DNA damage and its combination with standard DNA damage-inducing chemotherapy prolongs survival in aggressive murine AML models. Our work supports developing FA desaturase inhibitors in AML while stressing the importance of identifying predictive biomarkers of response and biologically validated combination therapies to realize their therapeutic potential.KEY POINTSSCD expression is highly prognostic in AML and SCD inhibition is toxic in AML cells displaying high rates of fatty acid desaturation.SCD inhibition in combination with conventional chemotherapy prolongs survival in murine AML models.

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“…Interestingly, AML cells show dependence on FAO, even in the absence of treatment exposure, due to low levels of prolyl-hydroxylase 3 (PHD3), which is an activator of acetyl-CoA Carboxylase 2 (ACC2) that normally suppresses FAO. Furthermore, high expression levels of carnitine palmitoyl transferase 1A (CPT1A) and the carnitine transporter CT2 (SLC22A16) also contribute to promoting FAO and constitute therapeutic targets for AML subsets [23][24][25]. Very recently, LICs from relapsed/refractory (R/R) AML patients have been found to be different metabolically from the LICs of de novo AML patients [26].…”

Section: Deregulated Metabolic Programs In Leukemia 21 Glucose Metabolism: Warburg Effect and Metabolic Flexibilitymentioning

confidence: 99%

Insights on Metabolic Reprogramming and Its Therapeutic Potential in Acute Leukemia

Martino

Tosello

Peroni

et al. 2021

IJMS

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Acute leukemias, classified as acute myeloid leukemia and acute lymphoblastic leukemia, represent the most prevalent hematologic tumors in adolescent and young adults. In recent years, new challenges have emerged in order to improve the clinical effectiveness of therapies already in use and reduce their side effects. In particular, in this scenario, metabolic reprogramming plays a key role in tumorigenesis and prognosis, and it contributes to the treatment outcome of acute leukemia. This review summarizes the latest findings regarding the most relevant metabolic pathways contributing to the continuous growth, redox homeostasis, and drug resistance of leukemia cells. We describe the main metabolic deregulations in acute leukemia and evidence vulnerabilities that could be exploited for targeted therapy.

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The Role of Metabolism in the Development of Personalized Therapies in Acute Myeloid Leukemia

Cited by 7 publications

References 98 publications

EIF4A inhibition targets bioenergetic homeostasis in AML MOLM-14 cells in vitro and in vivo and synergizes with cytarabine and venetoclax

EIF4A inhibition targets bioenergetic homeostasis in AML MOLM-14 cells in vitro and in vivo and synergizes with cytarabine and venetoclax

SCD inhibition preferentially eradicates AML displaying high de novo fatty acid desaturation and synergizes with chemotherapy

Insights on Metabolic Reprogramming and Its Therapeutic Potential in Acute Leukemia

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