Systemic Metabolomic Profiling of Acute Myeloid Leukemia Patients before and During Disease-Stabilizing Treatment Based on All-Trans Retinoic Acid, Valproic Acid, and Low-Dose Chemotherapy

Grønningsæter, Ida Sofie; Fredly, Hanne; Gjertsen, Bjørn Tore; Hatfield, Kimberley Joanne; Bruserud, Øystein

doi:10.3390/cells8101229

Cited by 20 publications

(23 citation statements)

References 80 publications

(130 reference statements)

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“…Possible strategies could then be treatment with metformin and statins [60,61]. However, another alternative could be treatment with valproic acid that alters metabolic profiles, especially levels of several lipids/fatty acids and amino acid metabolites [62]. Thus, combined direct and indirect metabolic targeting of the AML cells may be an alternative treatment option.…”

Section: Discussionmentioning

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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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%

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

Grønningsæter

Reikvam

Aasebø

et al. 2020

Cells

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“…Mutations in membrane bound-proteins, such as RTKs or GTPases, are major causes of dysregulated PI3K-Akt-mTOR signaling and are observed in 55% of AML cases [13,66]. However, no available data indicate that PI3K-Akt-mTOR activity is related to specific etiology of the disease, i.e., de novo, secondary or refractory/relapsed AML, nor to specific molecular subtypes, i.e., nucleophosmin 1 (NPM1) or fms like tyrosine kinase 3 (FLT3) mutations or other cytogenetic or molecular genetic alterations [84][85][86].…”

Section: Pi3k-akt-mtor Signaling In Amlmentioning

confidence: 99%

The PI3K-Akt-mTOR Signaling Pathway in Human Acute Myeloid Leukemia (AML) Cells

Nepstad

Hatfield

Grønningsæter

et al. 2020

IJMS

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188

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Acute myeloid leukemia (AML) is a heterogeneous group of diseases characterized by uncontrolled proliferation of hematopoietic stem cells in the bone marrow. Malignant cell growth is characterized by disruption of normal intracellular signaling, caused by mutations or aberrant external signaling. The phosphoinositide 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) pathway (PI3K-Akt-mTOR pathway) is among one of the intracellular pathways aberrantly upregulated in cancers including AML. Activation of this pathway seems important in leukemogenesis, and given the central role of this pathway in metabolism, the bioenergetics of AML cells may depend on downstream signaling within this pathway. Furthermore, observations suggest that constitutive activation of the PI3K-Akt-mTOR pathway differs between patients, and that increased activity within this pathway is an adverse prognostic parameter in AML. Pharmacological targeting of the PI3K-Akt-mTOR pathway with specific inhibitors results in suppression of leukemic cell growth. However, AML patients seem to differ regarding their susceptibility to various small-molecule inhibitors, reflecting biological heterogeneity in the intracellular signaling status. These findings should be further investigated in both preclinical and clinical settings, along with the potential use of this pathway as a prognostic biomarker, both in patients receiving intensive curative AML treatment and in elderly/unfit receiving AML-stabilizing treatment.

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“…Several cytokines could be constitutively released by AML blasts [ 16 ] and are important for intercellular communication in the bone marrow microenvironment [ 29 ]. Metabolic targeting is now considered as a therapeutic strategy in human malignancies, including AML [ 57 ]. This is especially true for the 10–15% of AML patients with mutations in the metabolic genes isocitrate dehydrogenase ( IDH ) 1 or 2, resulting in increased levels of oncometabolites [ 58 ].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of NF-κB Signaling Alters Acute Myelogenous Leukemia Cell Transcriptomics

Reikvam

2020

Cells

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Acute myelogenous leukemia (AML) is an aggressive hematological malignancy. The pathophysiology of the disease depends on cytogenetic abnormalities, gene mutations, aberrant gene expressions, and altered epigenetic regulation. Although new pharmacological agents have emerged during the last years, the prognosis is still dismal and new therapeutic strategies are needed. The transcription factor nuclear factor-κB (NF-κB) is regarded a possible therapeutic target. In this study, we investigated the alterations in the global gene expression profile (GEP) in primary AML cells derived from 16 consecutive patients after exposure to the NF-κB inhibitor BMS-345541. We identified a profound and highly discriminative transcriptomic profile associated with NF-κB inhibition. Bioinformatical analyses identified cytokine/interleukin signaling, metabolic regulation, and nucleic acid binding/transcription among the major biological functions influenced by NF-κB inhibition. Furthermore, several key genes involved in leukemogenesis, among them RUNX1 and CEBPA, in addition to NFKB1 itself, were influenced by NF-κB inhibition. Finally, we identified a significant impact of NF-κB inhibition on the expression of genes included in a leukemic stem cell (LSC) signature, indicating possible targeting of LSCs. We conclude that NF-κB inhibition significantly altered the expression of genes central to the leukemic process.

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Systemic Metabolomic Profiling of Acute Myeloid Leukemia Patients before and During Disease-Stabilizing Treatment Based on All-Trans Retinoic Acid, Valproic Acid, and Low-Dose Chemotherapy

Cited by 20 publications

References 80 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 PI3K-Akt-mTOR Signaling Pathway in Human Acute Myeloid Leukemia (AML) Cells

Inhibition of NF-κB Signaling Alters Acute Myelogenous Leukemia Cell Transcriptomics

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