Identification of CKMT1B As a New Target in EVI1-Positive AML

Abstract Recent investigations into the relationship between cancer and cellular metabolism have revealed the strong dependency of different cancers on a diverse array of metabolic pathways. For instance, a variety of cancers depend on the PI3K/AKT pathway for a wide range of glucose-related mechanisms, including AKT-mediated membrane translocation of glucose transporters, activation of the glycolytic enzymes hexokinase and phosphofructokinase, and up-regulation of de novo fatty acid synthesis. A major area of therapeutic and biological interest in the study of cancer metabolism is the process by which these metabolic pathways become deregulated in the first place en route to, or as a result of, the development of cancer. The deregulation of metabolic pathways can occur through alterations in the cellular landscape brought about by mutations in metabolic enzymes (e.g., IDH1/IDH2 and SDH), aberrant expression of transcription factors, such as the proto-oncogene MYC, or the loss of tumor suppressors, such as p53. Through gene expression and metabolic profiling analyses, we found that the transcription factor EVI-1, whose overexpression in acute and chronic myeloid leukemia (AML and CML) is correlated with poor patient outcome, induced key metabolic perturbations in hematopoietic progenitor cells. These result in a decrease of the mitochondrial oxygen consumption rate, a blockade of the de novo purine and pyrimidine synthesis, and an increase in glycolysis. Using a library of pooled shRNAs targeting genes involved in each of these pathways, we then established a direct link between EVI-1 expression and the development of a heretofore undescribed cellular dependency on the overexpression of the ATP-buffering mitochondrial creatine kinase protein CKMT1B. We showed that EVI-1 directly promotes CKMT1B expression through repression of the master regulator of myeloid differentiation RUNX1. Alteration of the CKMT1B-dependent pathway, either with shRNA or with the small molecule cyclocreatine, impairs production of intracellular phospho-creatine, which in turn alters cell viability specifically in EVI-1-positive (n = 8) versus EVI-1-negative AML cell lines (n = 8), and in EVI-1-positive (n = 5) versus EVI-1-negative (n = 17) primary AML blasts. This decrease in cell viability is associated with the activation of an erythroid differentiation program concomitant with a downregulation of the immature lineage marker c-KIT, both induced by GSK3A/B inhibition. Overexpression of a constitutively activated form of GSK3B (S9A) or GSK3A (S21A) impairs the cell differentiation induced by CKMT1B inhibition. Finally, suppression of CKMT1B alleviates leukemic burden in vivo in two AML mouse models: i) an orthotopic model of transplanted human EVI1-positive AML cells and ii) a syngeneic model of transplanted murine NrasG12D + Evi1 AML cells. This new interplay between EVI-1 and the creatine pathway uncovers CKMT1B as a new target of interest in EVI-1-positive AML, a high-risk subtype of AML for which current treatment regimens remain inadequate. Disclosures DeAngelo: Novartis: Consultancy; Ariad: Consultancy; Bristol Myers Squibb: Consultancy; Pfizer: Consultancy; Amgen: Consultancy; Incyte: Consultancy; Agios: Consultancy; Celgene: Consultancy. Stone:Celgene: Consultancy; Agios: Consultancy; Karyopharm: Consultancy; Sunesis: Consultancy, Other: DSMB for clinical trial; Novartis: Research Funding; Celator: Consultancy; Merck: Consultancy; Roche/Genetech: Consultancy; Abbvie: Consultancy; Amgen: Consultancy; Pfizer: Consultancy; AROG: Consultancy; Juno: Consultancy. Stegmaier:Novartis Pharmaceuticals: Consultancy.

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Development of cancer metabolism as a therapeutic target: new pathways, patient studies, stratification and combination therapy

British Journal of Cancer ◽

10.1038/s41416-019-0666-4 ◽

2019 ◽

Vol 122 (1) ◽

pp. 1-3 ◽

Cited By ~ 4

Author(s):

Adrian L. Harris

Keyword(s):

Metabolic Pathways ◽

Trial Design ◽

Cancer Metabolism ◽

Aerobic Glycolysis ◽

Critical Role ◽

Therapeutic Approaches ◽

Preclinical Models ◽

Wide Range ◽

Patient Studies

AbstractCancer metabolism has undergone a resurgence in the last decade, 70 years after Warburg described aerobic glycolysis as a feature of cancer cells. A wide range of techniques have elucidated the complexity and heterogeneity in preclinical models and clinical studies. What emerges are the large differences between tissues, tumour types and intratumour heterogeneity. However, synergies with inhibition of metabolic pathways have been found for many drugs and therapeutic approaches, and a critical role of window studies and translational trial design is key to success.

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De novo design of self-assembling helical protein filaments

Science ◽

10.1126/science.aau3775 ◽

2018 ◽

Vol 362 (6415) ◽

pp. 705-709 ◽

Cited By ~ 48

Author(s):

Hao Shen ◽

Jorge A. Fallas ◽

Eric Lynch ◽

William Sheffler ◽

Bradley Parry ◽

...

Keyword(s):

De Novo ◽

Computational Design ◽

Building Blocks ◽

Repeat Units ◽

Self Assembling ◽

Wide Range ◽

Helical Protein ◽

Monomeric Proteins

We describe a general computational approach to designing self-assembling helical filaments from monomeric proteins and use this approach to design proteins that assemble into micrometer-scale filaments with a wide range of geometries in vivo and in vitro. Cryo–electron microscopy structures of six designs are close to the computational design models. The filament building blocks are idealized repeat proteins, and thus the diameter of the filaments can be systematically tuned by varying the number of repeat units. The assembly and disassembly of the filaments can be controlled by engineered anchor and capping units built from monomers lacking one of the interaction surfaces. The ability to generate dynamic, highly ordered structures that span micrometers from protein monomers opens up possibilities for the fabrication of new multiscale metamaterials.

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Protective Effect of Opuntia dillenii Haw Fruit against Lead Acetate-Induced Hepatotoxicity: In Vitro and In Vivo Studies

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2021/6698345 ◽

2021 ◽

Vol 2021 ◽

pp. 1-13

Author(s):

Reza Shirazinia ◽

Ali Akbar Golabchifar ◽

Vafa Baradaran Rahimi ◽

Abbas Jamshidian ◽

Alireza Samzadeh-Kermani ◽

...

Keyword(s):

Cell Viability ◽

Lead Acetate ◽

Male Rats ◽

Tnf Α ◽

Wide Range ◽

Hepatoprotective Effects ◽

Anti Inflammatory ◽

Opuntia Dillenii

Lead is one of the most common environmental contaminants in the Earth’s crust, which induces a wide range of humans biochemical changes. Previous studies showed that Opuntia dillenii (OD) fruit possesses several antioxidant and anti-inflammatory properties. The present study evaluates OD fruit hydroalcoholic extract (OHAE) hepatoprotective effects against lead acetate- (Pb-) induced toxicity in both animal and cellular models. Male rats were grouped as follows: control, Pb (25 mg/kg/d i.p.), and groups 3 and 4 received OHAE at 100 and 200 mg/kg/d + Pb (25 mg/kg/d i.p.), for ten days of the experiment. Thereafter, we evaluated the levels of alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST), catalase (CAT) activity and malondialdehyde (MDA) in serum, and liver histopathology. Additionally, the cell study was also done using the HepG2 cell line for measuring the direct effects of the extract on cell viability, oxidative stress MDA, and glutathione (GSH) and inflammation tumor necrosis factor-α (TNF-α) following the Pb-induced cytotoxicity. Pb significantly increased the serum levels of ALT, AST, ALP, and MDA and liver histopathological scores but notably decreased CAT activity compared to the control group ( p < 0.001 for all cases). OHAE (100 and 200 mg/kg) significantly reduced the levels of serum liver enzyme activities and MDA as well as histopathological scores while it significantly increased CAT activity compared to the Pb group ( p < 0.001 –0.05 for all cases). OHAE (20, 40, and 80 μg/ml) concentration dependently and significantly reduced the levels of MDA and TNF-α, while it increased the levels of GSH and cell viability in comparison to the Pb group ( p < 0.001 –0.05 for all cases). These data suggest that OHAE may have hepatoprotective effects against Pb-induced liver toxicity both in vitro and in vivo by its antioxidant and anti-inflammatory activities.

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Characterization of Metabolites of α-mangostin in Bio-samples from SD Rats by UHPLC-Q-Exactive Orbitrap MS

Current Drug Metabolism ◽

10.2174/1389200222666211126093124 ◽

2021 ◽

Vol 22 ◽

Author(s):

Fan Dong ◽

Shaoping Wang ◽

Ailin Yang ◽

Haoran Li ◽

Pingping Dong ◽

...

Keyword(s):

Metabolic Pathways ◽

Garcinia Mangostana ◽

Sd Rats ◽

Metabolic Route ◽

Wide Range ◽

New Strategy ◽

Q Exactive ◽

Orbitrap Ms

Background: α-mangostin, a typical xanthone, often exists in Garcinia mangostana L. (Clusiaceae). α-mangostin was found to have a wide range of pharmacological properties. However, its specific metabolic route in vivo remains unclear, while these metabolites may accumulate to exert pharmacological effects, too. Objective: This study aimed to clarify the metabolic pathways of α-mangostin after oral administration to the rats. Methods: Here, an UHPLC-Q-Exactive Orbitrap MS was used for the detection of potential metabolites formed in vivo. A new strategy for the identification of unknown metabolites based on typical fragmentation routes was implemented. Results: A total of 42 metabolites were detected, and their structures were tentatively identified in this study. The results showed that major in vivo metabolic pathways of α-mangostin in rats included methylation, demethylation, methoxylation, hydrogenation, dehydrogenation, hydroxylation, dehydroxylation, glucuronidation, and sulfation. Conclusions: This study is significant to expand our knowledge of the in vivo metabolism of α-mangostin and to understand the mechanism of action of α-mangostin in rats in vivo.

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Quantitative analysis of Mycobacterium avium subsp. hominissuis proteome in response to antibiotics and during exposure to different environmental conditions

Clinical Proteomics ◽

10.1186/s12014-019-9260-2 ◽

2019 ◽

Vol 16 (1) ◽

Cited By ~ 5

Author(s):

Rajoana Rojony ◽

Matthew Martin ◽

Anaamika Campeau ◽

Jacob M. Wozniak ◽

David J. Gonzalez ◽

...

Keyword(s):

Quantitative Analysis ◽

Mycobacterium Avium ◽

Metabolic Pathways ◽

De Novo ◽

Aerobic Condition ◽

Peptidoglycan Biosynthesis ◽

Tandem Mass Tag ◽

Drug Treatments ◽

The Common

Abstract Mycobacterium avium subsp. hominissuis (MAH) belongs to the clinically important non-tuberculous mycobacterial group that infects immunocompromised patients and individuals with underling lung conditions. The need for prolonged therapy is a major challenge of MAH treatment, influencing the development of persistent and drug-resistant infections. The reason why bactericidal drugs take several months to eliminate MAH is unknown. To investigate MAH proteome remodeling under aerobic, anaerobic and biofilm conditions (as it is encountered in patient lungs) and identify metabolic changes potentially associated with bacterial persistent state, we performed the relative protein quantitative analysis using Tandem Mass Tag Mass Spectrometry sequencing. MAH was exposed to amikacin (4 μg/ml) and clarithromycin (16 μg/ml) under aerobic, anaerobic or biofilm condition for 24 h and the response was compared with bacterial proteomics of the corresponding conditions. Overall, 4000 proteins were identified out of 5313 MAH proteome of across all experimental groups. Numerous sets of de novo synthesized proteins belonging to metabolic pathways not evidenced in aerobic condition were found commonly enriched in both anaerobic and biofilm conditions, including pantothenate and CoA biosynthesis, glycerolipid metabolism, nitrogen metabolism and chloroalkene degradation, known to be associated with bacterial tolerance in M. tuberculosis. The common pathways observed in anaerobic and biofilm conditions following drug treatments were peptidoglycan biosynthesis, glycerophospholipid metabolism and protein export. The LprB lipoprotein, highly synthesized in MAH biofilms during drug treatments and shown to be essential for M. tuberculosis virulence and survival in vivo, was selected and overexpressed in MAH. Results demonstrate that LprB is secreted in MAH biofilms and the overexpression clone is more tolerant to antimicrobials than the wild-type strain. Our study identified promising metabolic pathways that can be targeted to prevent the bacterial tolerance mechanism and, subsequently, reduce the length of MAH therapy.

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High incidence of cytomegalovirus infection after nonmyeloablative stem cell transplantation: potential role of Campath-1H in delaying immune reconstitution

Blood ◽

10.1182/blood.v99.12.4357 ◽

2002 ◽

Vol 99 (12) ◽

pp. 4357-4363 ◽

Cited By ~ 294

Author(s):

Suparno Chakrabarti ◽

Stephen Mackinnon ◽

Raj Chopra ◽

Panagiotis D. Kottaridis ◽

Karl Peggs ◽

...

Keyword(s):

Immune Reconstitution ◽

De Novo ◽

Unrelated Donor ◽

Cmv Infection ◽

Nonmyeloablative Stem Cell Transplantation ◽

Wide Range ◽

Significant Difference ◽

High Incidence ◽

Cmv Disease

Nonmyeloablative conditioning is increasingly used for transplantation in a wide range of diseases, but little is known about its impact on the incidence of infections and immune reconstitution. We examined the pattern and outcome of cytomegalovirus (CMV) infections monitored by polymerase chain reaction–based assays and treated preemptively in 101 patients following nonmyeloablative conditioning containing in vivo Campath-1H. Fifty-one patients (50%) had a CMV infection at a median of 27 days after transplantation with a probability of 84.8% in patients at risk of CMV infection. The probability of recurrence of CMV infection before and after 100 days was 53.6% and 46.6%, respectively, and was more common in unrelated donor transplant recipients. All 3 patients who developed CMV disease died of this complication. The 2 patients with late CMV disease had grade III to IV graft-versus-host-disease (GVHD), which occurred de novo in only 4% of patients and in another 10% following donor lymphocyte infusions. The median time to CD4+ T-cell count more than 200/μL was 9 months in the 48 patients studied. The probabilities of overall survival and nonrelapse mortality at 18 months were 65% and 27.8%, respectively, with no significant difference in survival between CMV-infected and -uninfected patients. The use of Campath-1H appeared to be associated with a low incidence of GVHD but a high incidence of CMV infections and prolonged immune paresis.

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USP22-dependent accumulation of lipidomes drives hepatocellular carcinoma progression by stabilizing PPARγ

10.21203/rs.3.rs-82450/v1 ◽

2020 ◽

Author(s):

Zhen Ning ◽

Xin Guo ◽

Xiaolong Liu ◽

Chang Lu ◽

Aman Wang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Fatty Acid ◽

Molecular Mechanism ◽

Fatty Acid Synthesis ◽

De Novo ◽

Acid Synthesis ◽

Specific Protease ◽

Pparγ Expression

Abstract Elevated de novo lipogenesis (DNL) is considered to be a crucial factor in hepatocellular carcinoma (HCC) development. However, the molecular mechanism for its occurrence in HCC is still unclear. Herein, we identified ubiquitin-specific protease 22 (USP22) as a key regulator for de novo fatty acid synthesis, which directly interacts with, deubiquitinates and stabilizes PPARγ through K48-linked deubiquitination, and in turn, this stabilization increases ACC and ACLY transcription. In addition, we found that USP22 promoted the de novo synthesis of fatty acid labeling from glucose tracers. USP22-dysregulated de novo fatty acid synthesis contributes to HCC progression, but USP22 was functionality suppressed by inhibiting the expression of PPARγ, ACLY, or ACC in in vitro cell proliferation and in vivo tumorigenesis experiments. In HCC, USP22 expression positively correlates with PPARγ expression, and simultaneously, high expression of USP22 and PPARγ or USP22, ACC and ACLY is associated with a poor prognosis. Taken together, we identified a previously undescribed USP22-regulated lipogenesis molecular mechanism that involves the PPARγ-ACLY/ACC axis in HCC tumorigenesis and provide a rationale for therapeutic targeting of lipogenesis via USP22 inhibition.

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MO006CHANGES IN THE KYNURENINE PATHWAY LEAD TO ALTERATIONS IN NAD BALANCE AND BIOENERGETICS PARAMETERS IN GLOMERULAR CELLS IN VITRO AND CONTRIBUTE TO PROTEINURIA IN A ZEBRAFISH MODEL*

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfab079.002 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

Patricia Bolanos-Palmieri ◽

Ahmed Kotb ◽

Heiko Schenk ◽

Heike Bähre ◽

Patricia Schroder ◽

...

Keyword(s):

Mitochondrial Membrane ◽

De Novo ◽

Kynurenine Pathway ◽

Mass Spectrometry Analysis ◽

Bioactive Metabolites ◽

Enzymatic Function ◽

Wide Range ◽

Tryptophan Catabolism

Abstract Background and Aims Tryptophan catabolism is carried out by the enzymes of the kynurenine pathway leading to the de novo synthesis of NAD and the production of a series of bioactive metabolites. Kynurenine 3-Monooxigenase (KMO) is a key component of this pathway and it is one of the enzymes responsible for the degradation of kynurenine. The kynurenine metabolites participate in various cellular processes, so systemic dysregulation of tryptophan metabolism, marked by increased kynurenine in the circulation, has been linked to the onset and severity of a wide range of pathologies, such as chronic kidney disease and associated co-morbidities. Since the enzymes of the kynurenine pathway are expressed in the kidney and the metabolites are cleared in the urine, we aim to describe the effects of changes in tryptophan catabolism on glomerular cells, both in vitro and in vivo. Method Modulation of KMO expression or enzymatic function was performed in a transgenic zebrafish line that allows for the monitoring of a fluorescently labelled protein in the circulation as an indicator for proteinuria. Morpholinos targeting three enzymes of the kynurenine pathway were injected into fish embryos, leading to a knockdown of Afmid, Kmo and Kynu. Additionally, dechorionated larvae were treated with a Kmo inhibitor administered via the embryo rearing media, starting at 48hpf. In all cases at 96hpf, circulating fluorescent protein levels were determined, larval phenotype was scored based on the severity of the edema, and samples were collected for metabolite analysis or fixed and prepared for imaging. Since the kynurenine pathway results in the de novo production of NAD, and the enzyme KMO is located in the outer mitochondrial membrane, cultured murine parietal epithelial cells as well as immortalized human and mouse podocytes were incubated with a KMO inhibitor. Changes in NAD+ and NADH, as well as alterations in the mitochondrial membrane polarization were assessed. Additionally, the oxygen consumption rate was measured in order to determine if KMO inhibition leads to changes in the bioenergetics parameters of glomerular cells in vitro. Results The modification of Afmid, Kmo and Kynu expression levels by morpholino mediated knockdown or inhibition of Kmo lead to the accumulation of upstream kynurenine metabolites in the treated larvae, as was confirmed by mass spectrometry analysis. Following our previous results, alteration of the kynurenine pathway led to the development of yolk sac edema, pericardial effusion and loss of protein from the circulation, accompanied by an enlargement of the Bowman’s space and changes in nephrin expression in the glomerulus of the treated larvae. Under cell culture conditions, KMO inhibition in immortalized podocytes led to a reduction in cell size and focal adhesion proteins (podocalyxin). The NAD+/NADH ratio as well as mitochondrial membrane polarity were also altered. Additionally, changes in spare respiratory capacity, coupling efficiency and proton leak suggest that alterations in the kynurenine pathway might impair the cell’s ability to adapt its bioenergetic profile in response to stress. Conclusion Taken together these results suggest that the modulation of tryptophan catabolism through the kynurenine pathway may contribute to maintaining the structural integrity of glomerular cytoskeleton as well a flexible energy metabolism in podocytes. Moreover, the results from our in vivo model also suggest that imbalances in kynurenine metabolites might ultimately impact the function of the glomerular filtration barrier.

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The Effect of Fructose Feeding on Intestinal Triacylglycerol Production and De Novo Fatty Acid Synthesis in Humans

Nutrients ◽

10.3390/nu12061781 ◽

2020 ◽

Vol 12 (6) ◽

pp. 1781

Author(s):

Simon Steenson ◽

Fariba Shojaee-Moradie ◽

Martin B. Whyte ◽

Kim G. Jackson ◽

Julie A. Lovegrove ◽

...

Keyword(s):

De Novo ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Acid Synthesis ◽

Acute Effect ◽

De Novo Lipogenesis ◽

Fructose Intake ◽

High Fructose ◽

Catabolic Rate

A high fructose intake exacerbates postprandial plasma triacylglycerol (TAG) concentration, an independent risk factor for cardiovascular disease, although it is unclear whether this is due to increased production or impaired clearance of triacylglycerol (TAG)-rich lipoproteins. We determined the in vivo acute effect of fructose on postprandial intestinal and hepatic lipoprotein TAG kinetics and de novo lipogenesis (DNL). Five overweight men were studied twice, 4 weeks apart. They consumed hourly mixed-nutrient drinks that were high-fructose (30% energy) or low-fructose (<2% energy) for 11 h. Oral 2H2O was administered to measure fasting and postprandial DNL. Postprandial chylomicron (CM)-TAG and very low-density lipoprotein (VLDL)-TAG kinetics were measured with an intravenous bolus of [2H5]-glycerol. CM and VLDL were separated by their apolipoprotein B content using antibodies. Plasma TAG (p < 0.005) and VLDL-TAG (p = 0.003) were greater, and CM-TAG production rate (PR, p = 0.046) and CM-TAG fractional catabolic rate (FCR, p = 0.073) lower when high-fructose was consumed, with no differences in VLDL-TAG kinetics. Insulin was lower (p = 0.005) and apoB48 (p = 0.039), apoB100 (p = 0.013) and non-esterified fatty acids (NEFA) (p = 0.013) were higher after high-fructose. Postprandial hepatic fractional DNL was higher than intestinal fractional DNL with high-fructose (p = 0.043) and low-fructose (p = 0.043). Fructose consumption had no effect on the rate of intestinal or hepatic DNL. We provide the first measurement of the rate of intestinal DNL in humans. Lower CM-TAG PR and CM-TAG FCR with high-fructose consumption suggests lower clearance of CM, rather than elevated production, may contribute to elevated plasma TAG, possibly due to lower insulin-mediated stimulation of lipoprotein lipase.

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Capture at the single cell level of metabolic modules distinguishing aggressive and indolent glioblastoma cells

Acta Neuropathologica Communications ◽

10.1186/s40478-019-0819-y ◽

2019 ◽

Vol 7 (1) ◽

Cited By ~ 1

Author(s):

Mirca S. Saurty-Seerunghen ◽

Léa Bellenger ◽

Elias A. El-Habr ◽

Virgile Delaunay ◽

Delphine Garnier ◽

...

Keyword(s):

Single Cell ◽

Metabolic Pathways ◽

Acid Synthesis ◽

Chain Polyunsaturated Fatty Acid ◽

Glioblastoma Cell ◽

Sequencing Data ◽

Tumorigenic Potential ◽

Metabolism Enzymes ◽

Orthotopic Xenografts

Abstract Glioblastoma cell ability to adapt their functioning to microenvironment changes is a source of the extensive intra-tumor heterogeneity characteristic of this devastating malignant brain tumor. A systemic view of the metabolic pathways underlying glioblastoma cell functioning states is lacking. We analyzed public single cell RNA-sequencing data from glioblastoma surgical resections, which offer the closest available view of tumor cell heterogeneity as encountered at the time of patients’ diagnosis. Unsupervised analyses revealed that information dispersed throughout the cell transcript repertoires encoded the identity of each tumor and masked information related to cell functioning states. Data reduction based on an experimentally-defined signature of transcription factors overcame this hurdle. It allowed cell grouping according to their tumorigenic potential, regardless of their tumor of origin. The approach relevance was validated using independent datasets of glioblastoma cell and tissue transcriptomes, patient-derived cell lines and orthotopic xenografts. Overexpression of genes coding for amino acid and lipid metabolism enzymes involved in anti-oxidative, energetic and cell membrane processes characterized cells with high tumorigenic potential. Modeling of their expression network highlighted the very long chain polyunsaturated fatty acid synthesis pathway at the core of the network. Expression of its most downstream enzymatic component, ELOVL2, was associated with worsened patient survival, and required for cell tumorigenic properties in vivo. Our results demonstrate the power of signature-driven analyses of single cell transcriptomes to obtain an integrated view of metabolic pathways at play within the heterogeneous cell landscape of patient tumors.

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