Metabolic Plasticity of Acute Myeloid Leukemia

Kreitz, Johanna; Schönfeld, Christine; Seibert, Marcel; Stolp, Verena; Alshamleh, Islam; Oellerich, Thomas; Steffen, Björn; Schwalbe, Harald; Schnütgen, Frank; Kurrle, Nina; Serve, Hubert

doi:10.3390/cells8080805

Cited by 115 publications

(124 citation statements)

References 126 publications

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“…Recent studies suggest that AML cells have considerably metabolic plasticity [9] and our present study shows that AML cells derived from different patients are also characterized by metabolic heterogeneity, that is the antiproliferative and proapoptotic effects of various metabolic inhibitors varied between patients. This was seen after treatment with inhibitors of glycolysis but also after targeting of mitochondrial metabolism through inhibition of glutaminolysis and fatty acid oxidation.…”

Section: Discussionsupporting

confidence: 51%

“…Complex metabolic capacities may contribute to the aggressiveness of AML, allowing cells to survive under higher metabolic demands. However, AML patients are heterogeneous with regard to metabolic regulation [8][9][10][11][12] and in this study we attempt to further investigate if patients are heterogeneous also with regard to the antileukemic effects of metabolic targeting.…”

Section: Introductionmentioning

confidence: 99%

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Targeting Cellular Metabolism in Acute Myeloid Leukemia and the Role of Patient Heterogeneity

Grønningsæter

Reikvam

Aasebø

et al. 2020

Cells

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Acute myeloid leukemia (AML) is an aggressive blood cancer resulting in accumulation of immature, dysfunctional blood cells in the bone marrow. Changes in cell metabolism are features of many cancers, including AML and this may be exploited as a therapeutic target. In this study we investigated the in vitro antileukemic effects of seven metabolic inhibitors that target different metabolic pathways. The metabolic inhibitors were tested on AML cells derived from 81 patients using proliferation and viability assays; we also compared global gene expression and proteomic profiles for various patient subsets. Metformin, 2DG, 6AN, BPTES and ST1326 had strong antiproliferative and proapoptotic effects for most patients, whereas lonidamine and AZD3965 had an effect only for a minority. Antiproliferative effects on AML cells were additive when combined with the chemotherapeutic agent AraC. Using unsupervised hierarchical clustering, we identified a strong antiproliferative effect on AML cells after treatment with metabolic inhibitors for a subset of 29 patients. Gene expression and proteomic studies suggested that this subset was characterized by altered metabolic and transcriptional regulation. In addition, the Bcl-2 inhibitor venetoclax, in combination with 2DG or 6AN, increased the antiproliferative effects of these metabolic inhibitors on AML cells. Therapeutic targeting of cellular metabolism may have potential in AML, but the optimal strategy will likely differ between patients.

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Section: Discussionsupporting

confidence: 51%

Section: Introductionmentioning

confidence: 99%

Targeting Cellular Metabolism in Acute Myeloid Leukemia and the Role of Patient Heterogeneity

Grønningsæter

Reikvam

Aasebø

et al. 2020

Cells

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“…1,2 The current progresses in AML mainly include improvements on treating opportunistic infectious diseases, advances on supportive care, and reduce of complications after allogeneic BM transplantation; however, the therapeutic effects are unsatisfactory, with a 5-year survival rate of 40% for younger patients (18-60 years) and a 5-year survival rate of 10% for the elder patients (age above 60 years), and AML is still a life-threatening disease. 1,3,4 Thus, rational development of novel strategies to improve the treatment outcomes of AML is important. Since emerging studies have revealed that the association of molecular aberrations with the prognosis may contribute to guide therapeutic decisions, exploring novel biomarkers that being identified for AML prognosis is desperately needed.…”

Section: Introductionmentioning

confidence: 99%

Identification of long non‐coding RNA MVIH as a prognostic marker and therapeutic target in acute myeloid leukemia

Jiang¹,

Luo³

2019

Clinical Laboratory Analysis

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Background: This study aimed to investigate the correlation of long non-coding RNA microvascular invasion in hepatocellular carcinoma (lncRNA MVIH) with disease risk, disease conditions, and prognosis of acute myeloid leukemia (AML), and also to investigate the influence of lncRNA MVIH on AML cell activities in vitro. Methods:A total of 212 AML patients and 70 controls were consecutively recruited.Their bone marrow mononuclear cells (BMMCs) were isolated, and lncRNA MVIH was detected by reverse transcription quantitative-polymerase chain reaction. In AML patients, complete remission (CR), event-free survival (EFS), and overall survival (OS) were assessed. In vitro, lncRNA MVIH expression in AML cell lines was determined, and the effect of lncRNA MVIH on AML cell proliferation and apoptosis was assessed.Results: LncRNA MVIH expression was increased in AML patients compared to controls, and receiver operating characteristic curve showed that lncRNA MVIH predicted elevated AML risk (area under curve: 0.742 [95% CI: 0.674-0.810]). In AML patients, no correlation of lncRNA MVIH expression with French-American-British classification was observed, while lncRNA MVIH high expression correlated with worse risk stratification. Moreover, lncRNA MVIH expression negatively correlated with CR achievement, EFS and OS. In vitro, lncRNA MVIH was overexpressed in AML cell lines (KG-1, ME-1, and HT-93) compared to normal BMMCs. Furthermore, lncRNA MVIH downregulation reduced KG-1 cell proliferation but increased apoptosis, whereas lncRNA MVIH upregulation raised HL-60 cell proliferation but decreased apoptosis.Conclusion: LncRNA MVIH may not only serve as a prognostic marker but also act as a therapeutic target in AML. K E Y W O R D Sacute myeloid leukemia, cell apoptosis, long non-coding RNA microvascular invasion in hepatocellular carcinoma, risk stratification, survival

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“…A wide variety of drugs used to treat cancers target actively proliferating cells (e.g., taxanes like paclitaxel or docetaxel, or cyclin-dependent kinase inhibitors like abemaciclib or palbociclib), making them less effective against LSCs. Importantly, LSCs, like other leukemia cells appear to be more dependent upon mitochondria for energy production than most cancer cells (60)(61)(62), and thus may be more sensitive to the drug cocktails identified here. This hypothesis is currently under active investigation.…”

Section: Discussionmentioning

confidence: 87%

Utilizing Synergistic Potential of Mitochondria-Targeting Drugs for Leukemia Therapy

et al. 2020

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Acute myeloid leukemia (AML) is an aggressive group of cancers with high mortality rates and significant relapse risks. Current treatments are insufficient, and new therapies are needed. Recent discoveries suggest that AML may be particularly sensitive to chemotherapeutics that target mitochondria. To further investigate this sensitivity, six compounds that target mitochondria [IACS-010759, rotenone, cytarabine, etoposide, ABT-199 (venetoclax), and carbonyl cyanide m-chlorophenylhydrazone] were each paired with six compounds with other activities, including tyrosine kinase inhibitors (midostaurin and dasatinib), glycolytic inhibitors (2-deoxy-D-glucose, 3-bromopyruvate, and lonidamine), and the microtubule destabilizer vinorelbine. The 36 resulting drug combinations were tested for synergistic cytotoxicity against MOLM-13 and OCI-AML2 AML cell lines. Four combinations (IACS-010759 with vinorelbine, rotenone with 2-deoxy-D-glucose, carbonyl cyanide m-chlorophenylhydrazone with dasatinib, and venetoclax with lonidamine) showed synergistic cytotoxicity in both AML cell lines and were selective for tumor cells, as survival of healthy PBMCs was dramatically higher. Among these drug pairs, IACS-010759/vinorelbine decreased ATP level and impaired mitochondrial respiration and coupling efficiency most profoundly. Some of these four treatments were also effective in K-562, KU812 (chronic myelogenous leukemia) and CCRF-CEM, MOLT-4 (acute lymphoblastic leukemia) cells, suggesting that these treatments may have value in treating other forms of leukemia. Finally, two of the four combinations retained high synergy and strong selectivity in primary AML cells from patient samples, supporting the potential of these treatments for patients.

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Metabolic Plasticity of Acute Myeloid Leukemia

Cited by 115 publications

References 126 publications

Targeting Cellular Metabolism in Acute Myeloid Leukemia and the Role of Patient Heterogeneity

Targeting Cellular Metabolism in Acute Myeloid Leukemia and the Role of Patient Heterogeneity

Identification of long non‐coding RNA MVIH as a prognostic marker and therapeutic target in acute myeloid leukemia

Utilizing Synergistic Potential of Mitochondria-Targeting Drugs for Leukemia Therapy

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