Glucose and Glutamine Metabolism Regulate Human Hematopoietic Stem Cell Lineage Specification

Oburoglu, Leal; Tardito, Saverio; Fritz, Vanessa; Barros, Stéphanie C. de; Mérida, Peggy; Craveiro, Marco; Mamede, João I.; Cretenet, Gaspard; Mongellaz, Cédric; An, Xiuli; Klysz, Dorota D.; Touhami, Jawida; Boyer-Clavel, Myriam; Battini, Jean-Luc; Dardalhon, Valérie; Zimmermann, Valérie S.; Mohandas, Narla; Gottlieb, Eyal; Sitbon, Marc; Kinet, Sandrina; Taylor, Naomi

doi:10.1016/j.stem.2014.10.009

Cited by 71 publications

(99 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We activated Ag-experienced T cells with Pam3 or with OVA 257-264 peptide in FCS-free, L-glutaminefree medium, and we compared their responsiveness to activation in L-glutamine-supplemented medium. Interestingly, regardless of the stimulus, L-glutamine significantly increased the ability of T cells to produce IFN-g. Again, addition of 6-diazo-5-oxo-Lnorleucine (DON), a glutamine antagonist that inhibits both glutamine uptake and glutaminolysis (48), reduced the responsiveness of T cells back to basal levels of the empty medium (Fig. 7C).…”

Section: Both Aerobic Glycolysis and Mitochondrial Respiration Generamentioning

confidence: 98%

TLR-Mediated Innate Production of IFN-γ by CD8+ T Cells Is Independent of Glycolysis

Salerno

Guislain

Cansever

et al. 2016

The Journal of Immunology

120

View full text Add to dashboard Cite

CD8+ T cells can respond to unrelated infections in an Ag-independent manner. This rapid innate-like immune response allows Ag-experienced T cells to alert other immune cell types to pathogenic intruders. In this study, we show that murine CD8+ T cells can sense TLR2 and TLR7 ligands, resulting in rapid production of IFN-γ but not of TNF-α and IL-2. Importantly, Ag-experienced T cells activated by TLR ligands produce sufficient IFN-γ to augment the activation of macrophages. In contrast to Ag-specific reactivation, TLR-dependent production of IFN-γ by CD8+ T cells relies exclusively on newly synthesized transcripts without inducing mRNA stability. Furthermore, transcription of IFN-γ upon TLR triggering depends on the activation of PI3K and serine-threonine kinase Akt, and protein synthesis relies on the activation of the mechanistic target of rapamycin. We next investigated which energy source drives the TLR-induced production of IFN-γ. Although Ag-specific cytokine production requires a glycolytic switch for optimal cytokine release, glucose availability does not alter the rate of IFN-γ production upon TLR-mediated activation. Rather, mitochondrial respiration provides sufficient energy for TLR-induced IFN-γ production. To our knowledge, this is the first report describing that TLR-mediated bystander activation elicits a helper phenotype of CD8+ T cells. It induces a short boost of IFN-γ production that leads to a significant but limited activation of Ag-experienced CD8+ T cells. This activation suffices to prime macrophages but keeps T cell responses limited to unrelated infections.

show abstract

Section: Both Aerobic Glycolysis and Mitochondrial Respiration Generamentioning

confidence: 98%

TLR-Mediated Innate Production of IFN-γ by CD8+ T Cells Is Independent of Glycolysis

Salerno

Guislain

Cansever

et al. 2016

The Journal of Immunology

120

View full text Add to dashboard Cite

show abstract

“…35 Glutamine metabolism also regulates human HSC lineage specification, as it was demonstrated that the SLC1A5 glutamine transporter is required for erythroid specification by regulating de novo nucleotide biosynthesis. 36 From the perspective of the therapeutic applications of GSL1 targeting in humans, we investigated the potential toxicity that results from GLS1 inhibition during normal hematopoiesis. Homozygous GLS1 deletion is lethal during the first postnatal day because of neurologic disorders.…”

Section: Addiction To Glutaminolysis In Aml 1349mentioning

confidence: 99%

Targeting glutaminolysis has antileukemic activity in acute myeloid leukemia and synergizes with BCL-2 inhibition

Jacque

Ronchetti

Larrue

et al. 2015

Blood

333

277

View full text Add to dashboard Cite

• Genetic-or compound CB-839-induced GAC inhibition reduces OXPHOS and has antileukemic activity in AML.• GAC inhibition synergizes with BCL-2 inhibition by compound ABT-199.Cancer cells require glutamine to adapt to increased biosynthetic activity. The limiting step in intracellular glutamine catabolism involves its conversion to glutamate by glutaminase (GA). Different GA isoforms are encoded by the genes GLS1 and GLS2 in humans. Herein, we show that glutamine levels control mitochondrial oxidative phosphorylation (OXPHOS) in acute myeloid leukemia (AML) cells. Glutaminase C (GAC) is the GA isoform that is most abundantly expressed in AML. Both knockdown of GLS1 expression and pharmacologic GLS1 inhibition by the drug CB-839 can reduce OXPHOS, leading to leukemic cell proliferation arrest and apoptosis without causing cytotoxic activity against normal human CD34 1 progenitors. Strikingly, GLS1 knockdown dramatically inhibited AML development in NSG mice. The antileukemic activity of CB-839 was abrogated by both the expression of a hyperactive GAC K320A allele and the addition of the tricarboxyclic acid cycle product a-ketoglutarate, indicating the critical function of GLS1 in AML cell survival. Finally, glutaminolysis inhibition activated mitochondrial apoptosis and synergistically sensitized leukemic cells to priming with the BCL-2 inhibitor ABT-199. These findings show that targeting glutamine addiction via GLS1 inhibition offers a potential novel therapeutic strategy for AML. (Blood. 2015;126(11):1346-1356

show abstract

“…On the other hand, intracellular glutamine is metabolized into α-ketoglutarate (α-KG) and ten-eleven translocation (TET) proteins, inducing epigenetic changes in an α-KG-dependent manner (described below). Glutamine is essential for HSC differentiation to erythroid lineage cells [51]. In terms of malignant hematopoiesis, asparagine-related pathways have been targeted as therapy in acute lymphocytic leukemia (ALL).…”

Section: Amino Acid-dependence Of Hscs and Leukemic Cellsmentioning

confidence: 99%

Metabolic regulation of hematopoietic and leukemic stem/progenitor cells under homeostatic and stress conditions

Karigane

Takubo

2017

Int J Hematol

View full text Add to dashboard Cite

organisms. HSPCs are composed of hematopoietic stem cells (HSCs) and several types of lineage-biased, but not fully committed, hematopoietic progenitor cells (HPCs). HSC capacities such as self-renewal and multilineage differentiation maintain the whole hematopoietic system over an organism's lifetime [1], and contribute to blood regeneration under stress condition, whereas HPCs reportedly function to maintain the supply of blood cells at steady state [2,3]. The surrounding BM microenvironment or "niche" determines HSC fate, namely its quiescence, symmetric/asymmetric division, differentiation, or migration potential, in both steady state and during stress. It is now evident that metabolic programs operating in HSCs play critical roles in maintaining hematopoietic homeostasis [4], often in response to BM niche signals [5]. Cellular pathways generate various metabolites through enzymatic activity that supplies material used as fuel, building blocks for other factors, or modulators of intra-or intercellular activities (Fig. 1). Despite the fact that numerous biochemical studies have addressed HSC metabolic regulation, numerous gaps in our knowledge of that regulation remain.Recently, novel means to fractionate metabolites using highly sensitive mass spectrometric technology [6] have dramatically facilitated metabolome analysis. These technologies reduce the need for high cell numbers and increase sensitivity of metabolite selection. As a result, metabolome analysis is feasible in rare cell populations such as HSCs. These analyses have revealed that metabolic programs play critical roles in maintaining stem cell "stemness" (Fig. 2). Here we review recent advances in the field of how metabolic changes regulate HSC dynamics under quiescence, proliferation, and differentiation from the viewpoint of each pathway. In addition to the normal HSC system, we also review activity of leukemia-related metabolic pathways, tumor-associated metabolites (oncometabolites), and Abstract Hematopoietic stem cells (HSCs) exhibit multilineage differentiation and self-renewal activities that maintain the entire hematopoietic system during an organism's lifetime. These abilities are sustained by intrinsic transcriptional programs and extrinsic cues from the microenvironment or niche. Recent studies using metabolomics technologies reveal that metabolic regulation plays an essential role in HSC maintenance. Metabolic pathways provide energy and building blocks for other factors functioning at steady state and in stress. Here we review recent advances in our understanding of metabolic regulation in HSCs relevant to cell cycle quiescence, symmetric/asymmetric division, and proliferation following stress and lineage commitment, and discuss the therapeutic potential of targeting metabolic factors or pathways to treat hematological malignancies.

show abstract

Glucose and Glutamine Metabolism Regulate Human Hematopoietic Stem Cell Lineage Specification

Cited by 71 publications

References 0 publications

TLR-Mediated Innate Production of IFN-γ by CD8+ T Cells Is Independent of Glycolysis

TLR-Mediated Innate Production of IFN-γ by CD8+ T Cells Is Independent of Glycolysis

Targeting glutaminolysis has antileukemic activity in acute myeloid leukemia and synergizes with BCL-2 inhibition

Metabolic regulation of hematopoietic and leukemic stem/progenitor cells under homeostatic and stress conditions

Contact Info

Product

Resources

About