The creatine kinase pathway is a metabolic vulnerability in EVI1-positive acute myeloid leukemia

Fenouille, Nina; Bassil, Christopher F.; Ben-Sahra, Issam; Benajiba, Lina; Alexe, Gabriela; Ramos, Azucena; Pikman, Yana; Conway, Amy Saur; Burgess, Michael R.; Li, Qing; Luciano, Fréderic; Auberger, Patrick; Galinsky, Ilene; DeAngelo, Daniel J.; Stone, Richard; Zhang, Yi; Perkins, Archibald S.; Shannon, Kevin; Hemann, Michael T.; Puissant, Alexandre; Stegmaier, Kimberly

doi:10.1038/nm.4283

Cited by 91 publications

(106 citation statements)

References 58 publications

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“…[46,47] SG animals also had an upregulation in MECOM regulated pathways, which are associated with increased purine and pyrimidine metabolism, amino acid metabolism, pentose phosphate pathway reliance, and glycolysis. [48]. Elevations in PPARg, SMRT, and NCOR which all interact to control downstream adipocyte fate and function, glucose handling, insulin sensitivity, mitochondrial oxidative capacity, and thermogenesis, were also found.…”

Section: Discussionmentioning

confidence: 94%

Sleeve Gastrectomy enhances glucose utilization and remodels adipose tissue independent of weight loss

Harris

Mina

Čabarkapa

et al. 2019

Preprint

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Objective: Sleeve gastrectomy (SG) induces weight-loss independent improvements in glucose homeostasis by unknown mechanisms. We sought to identify the metabolic adaptations responsible for these improvements.Methods: Non-obese C57Bl6/J mice on standard chow underwent SG or sham surgery. Functional testing and indirect calorimetry were used to capture metabolic phenotypes. Tissuespecific glucose uptake was assessed by 18-FDG PET/CT and RNA sequencing was used for gene expression analysis.Results: In this model, SG induced durable improvements in glucose tolerance despite not causing lasting changes in weight, fat/lean mass, or food intake. Indirect calorimetry revealed post-SG animals had respiratory exchange ratios (RER) nearing 1.0 on average and had daily RER excursions above 1.0, indicating preferential glucose utilization and increased energy demand, respectively. Sham operated mice demonstrate normal RER feeding/fasting excursions. PET/CT showed increased avidity within white adipose depots. Finally, SG led to an upregulation in the transcriptional pathways involved in energy metabolism, adipocyte maturation, and adaptive and innate immune cell chemotaxis and differentiation within the visceral adipose tissue.Conclusions: SG induces a rapid, weight-loss independent shift towards glucose utilization and transcriptional remodeling of metabolic and immune pathways in visceral adipose tissue.

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Section: Discussionmentioning

confidence: 94%

Sleeve Gastrectomy enhances glucose utilization and remodels adipose tissue independent of weight loss

Harris

Mina

Čabarkapa

et al. 2019

Preprint

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“…As a result, they demonstrated that SCC instead of AC has an amplified region of gene in 3q26.2–q29, where the EVI1 gene is located 10. Many previous studies have proved the oncogenic role of EVI1 in tumors, especially tumors of hematopoietic system 17. More and more emerging evidence has indicated the oncogenic role of EVI1 in solid tumors, including prostate cancer, ovarian cancer, glioblastoma, hepatocellular carcinoma, and so on 7,9,18.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of ecotropic viral integration site-1 is a prognostic factor of lung squamous cell cancer

Xu¹,

Liu

Xia³

2017

OTT

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AimTo explore the expression and clinical significance of ecotropic viral integration site-1 (EVI1) of lung squamous cell cancer (SCC).MethodsThe expression of EVI1 in SCC was detected by immunohistochemistry and the validation cohort was divided into EVI1 high-expression group and low-expression group according to the cutoff of immunohistochemical score. The correlations between EVI1 expression and the clinicopathological factors were analyzed by χ2 test. The relation between EVI1 expression and overall survival rate was evaluated by univariate analysis with Kaplan–Meier method. The independent prognostic factor was identified by multivariate analysis with Cox regression model.ResultsIn this study, the EVI1 high-expression percentage was 32.32% (53/164). EVI1 high expression was significantly associated with a poorer overall 5-year survival rate of SCC (P=0.021). Moreover, EVI1 high expression was identified as an independent prognostic factor of SCC, predicting the unfavorable prognosis (P=0.013).ConclusionHigh expression of EVI1 was significantly associated with a poorer prognosis and it was identified as an independent prognostic factor of SCC.

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“…KCRB depletion/inhibition in combination with chemotherapeutic agents showed synergistic effects in cancer therapy (47). Cr kinase metabolic inhibition by cc was shown to decrease cell viability, promote cell-cycle arrest, and apoptosis in EVI1 (48). Inhibition of the colon cancer cell line KCRB by preincubation with cc reduced liver metastasis formation and depleted PCr (49) and recently, mice inoculated with colorectal cancer cells and treated with cc showed a significant reduction in metastatic colonization (19).…”

Section: Discussionmentioning

confidence: 99%

Adaptation to HIF1α Deletion in Hypoxic Cancer Cells by Upregulation of GLUT14 and Creatine Metabolism

Valli

Morotti

Zois

et al. 2019

Molecular Cancer Research

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Hypoxia-inducible factor 1a is a key regulator of the hypoxia response in normal and cancer tissues. It is well recognized to regulate glycolysis and is a target for therapy. However, how tumor cells adapt to grow in the absence of HIF1a is poorly understood and an important concept to understand for developing targeted therapies is the flexibility of the metabolic response to hypoxia via alternative pathways. We analyzed pathways that allow cells to survive hypoxic stress in the absence of HIF1a, using the HCT116 colon cancer cell line with deleted HIF1a versus control. Spheroids were used to provide a 3D model of metabolic gradients. We conducted a metabolomic, transcriptomic, and proteomic analysis and integrated the results. These showed surprisingly that in three-dimensional growth, a key regulatory step of glycolysis is Aldolase A rather than phosphofructokinase. Furthermore, glucose uptake could be maintained in hypoxia through upregulation of GLUT14, not previously recognized in this role. Finally, there was a marked adaptation and change of phosphocreatine energy pathways, which made the cells susceptible to inhibition of creatine metabolism in hypoxic conditions. Overall, our studies show a complex adaptation to hypoxia that can bypass HIF1a, but it is targetable and it provides new insight into the key metabolic pathways involved in cancer growth.Implications: Under hypoxia and HIF1 blockade, cancer cells adapt their energy metabolism via upregulation of the GLUT14 glucose transporter and creatine metabolism providing new avenues for drug targeting. Analysis of the HCT116 hypoxic metabolic phenotype. A-C, Metabolomics-and proteomics-integrated circos-plots showing significantly regulated features only in KON versus WTN, WTH versus WTN, KOH versus KON, and KOH versus WTH (upper side circos-plots). Adjusted P < 0.05 ( Ã ) or P < 0.01 ( ÃÃ ) are indicated for the different experimental comparisons (connecting lines inside circos-plots): KON/WTN (gray/white-gray connection) WTH/WTN (gold/white-brown connection), KOH/KON (blue/gray-violet connection), KOH/WTH (blue/gold-green connection). Colored boxes (lower side circos-plots linked to connecting lines) represent different metabolic pathways, while colored boxes (inside circos-plots linked to connecting lines) identify the biological condition where the feature is upregulated. D, Heatmap of integrated transomics (proteomics and transcriptomics); mRNA and protein log 2 FC are calculated for WTH-WTN and KOH-WTH. Feature selection was based on departure from 95% confidence intervals of the linear model distribution built for each comparison (WTH-WTN and KOH-WTH). Metabolic pathways: glycogen (GLG), glycolysis (GLY), Krebs cycle (TCA), adenosine triphosphate (ATP), creatine (Cr), oxidation-reduction (REDOX), and adenosyl metabolism (ADE). E, Targeted metabolomics showing distribution of ATP, ADP, AMP, ATP/AMP, and ATP/ADP ratios in WTN, KON, WTH, and KOH cell after 24 hours in 21% and 1% O 2 . Raw intensities and ratios are shown as 0-1 normalized levels' rela...

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The creatine kinase pathway is a metabolic vulnerability in EVI1-positive acute myeloid leukemia

Cited by 91 publications

References 58 publications

Sleeve Gastrectomy enhances glucose utilization and remodels adipose tissue independent of weight loss

Sleeve Gastrectomy enhances glucose utilization and remodels adipose tissue independent of weight loss

Overexpression of ecotropic viral integration site-1 is a prognostic factor of lung squamous cell cancer

Adaptation to HIF1α Deletion in Hypoxic Cancer Cells by Upregulation of GLUT14 and Creatine Metabolism

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