Targeting Metabolic Reprogramming in Acute Myeloid Leukemia

Castro, Isabel; Sampaio‐Marques, Belém; Ludovico, Paula

doi:10.3390/cells8090967

Cited by 53 publications

(46 citation statements)

References 139 publications

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“…The metabolic status of AML cells can also be influenced by the amount of nutrients and metabolites in their microenvironment [9,10,46,60]. Modulation of systemic metabolic profiles may therefore be a strategy that indirectly affects the AML cells through alteration of their microenvironment.…”

Section: Discussionmentioning

confidence: 99%

“…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: Discussionmentioning

confidence: 99%

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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“…A large clinical study showed that the systemic levels of 14 glucose metabolites could be used to identify patients with an increased risk of later leukemia relapse [ 51 ]. Other studies also suggest that the AML cell metabolism and not only the systemic metabolic regulation differ between AML patients [ 48 , 67 , 68 ], but the possible prognostic impact of such differences needs further investigation.…”

Section: Aml Heterogeneity and Prognostic Evaluationmentioning

confidence: 99%

The Implementation of Mass Spectrometry-Based Proteomics Workflows in Clinical Routines of Acute Myeloid Leukemia: Applicability and Perspectives

Hernandez-Valladares

Bruserud

Selheim

2020

IJMS

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With the current reproducibility of proteome preparation workflows along with the speed and sensitivity of the mass spectrometers, the transition of the mass spectrometry (MS)-based proteomics technology from biomarker discovery to clinical implementation is under appraisal in the biomedicine community. Therefore, this technology might be implemented soon to detect well-known biomarkers in cancers and other diseases. Acute myeloid leukemia (AML) is an aggressive heterogeneous malignancy that requires intensive treatment to cure the patient. Leukemia relapse is still a major challenge even for patients who have favorable genetic abnormalities. MS-based proteomics could be of great help to both describe the proteome changes of individual patients and identify biomarkers that might encourage specific treatments or clinical strategies. Herein, we will review the advances and availability of the MS-based proteomics strategies that could already be used in clinical proteomics. However, the heterogeneity of complex diseases as AML requires consensus to recognize AML biomarkers and to establish MS-based workflows that allow their unbiased identification and quantification. Although our literature review appears promising towards the utilization of MS-based proteomics in clinical AML in a near future, major efforts are required to validate AML biomarkers and agree on clinically approved workflows.

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“…Metabolic reprogramming is recognized as a hallmark of cancer (184,185) and targeting metabolic pathways has been used for the treatment of various cancers to interfere with tumor progression (184,186). During bacterial infections of the lung the metabolic pathways of many immune cells are re-programmed to a more immunosuppressive phenotype, benefitting the bacteria and leading to chronic infection.…”

Section: Targeting Metabolic Changes Induced During Infectionmentioning

confidence: 99%

Target the Host, Kill the Bug; Targeting Host Respiratory Immunosuppressive Responses as a Novel Strategy to Improve Bacterial Clearance During Lung Infection

Kelly

McLoughlin

2020

Front. Immunol.

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The lung is under constant pressure to protect the body from invading bacteria. An effective inflammatory immune response must be tightly orchestrated to ensure complete clearance of any invading bacteria, while simultaneously ensuring that inflammation is kept under strict control to preserve lung viability. Chronic bacterial lung infections are seen as a major threat to human life with the treatment of these infections becoming more arduous as the prevalence of antibiotic resistance becomes increasingly commonplace. In order to survive within the lung bacteria target the host immune system to prevent eradication. Many bacteria directly target inflammatory cells and cytokines to impair inflammatory responses. However, bacteria also have the capacity to take advantage of and strongly promote anti-inflammatory immune responses in the host lung to inhibit local pro-inflammatory responses that are critical to bacterial elimination. Host cells such as T regulatory cells and myeloid-derived suppressor cells are often enhanced in number and activity during chronic pulmonary infection. By increasing suppressive cell populations and cytokines, bacteria promote a permissive environment suitable for their prolonged survival. This review will explore the anti-inflammatory aspects of the lung immune system that are targeted by bacteria and how bacterial-induced immunosuppression could be inhibited through the use of host-directed therapies to improve treatment options for chronic lung infections.

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Targeting Metabolic Reprogramming in Acute Myeloid Leukemia

Cited by 53 publications

References 139 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

The Implementation of Mass Spectrometry-Based Proteomics Workflows in Clinical Routines of Acute Myeloid Leukemia: Applicability and Perspectives

Target the Host, Kill the Bug; Targeting Host Respiratory Immunosuppressive Responses as a Novel Strategy to Improve Bacterial Clearance During Lung Infection

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