Glutamine metabolism, the Achilles heel for medulloblastoma tumor

Children with Cancer UK fellowship (Reference 2014/178

Hematopoietic stem cell lineage specification

PURPOSE OF REVIEW: Hematopoietic stem cells (HSCs) possess two fundamental characteristics, the capacity for self-renewal and the sustained production of all blood cell lineages. The fine balance between HSC expansion and lineage specification is dynamically regulated by the interplay between external and internal stimuli. This review introduces recent advances in the roles played by the stem cell niche, regulatory transcriptional networks, and metabolic pathways in governing HSC self-renewal, commitment, and lineage differentiation. We will further focus on discoveries made by studying hematopoiesis at single-cell resolution. RECENT FINDINGS: HSCs require the support of an interactive milieu with their physical position within the perivascular niche dynamically regulating HSC behavior. In these microenvironments, transcription factor networks and nutrient-mediated regulation of energy resources, signaling pathways, and epigenetic status govern HSC quiescence and differentiation. Once HSCs begin their lineage specification, single-cell analyses show that they do not become oligopotent but rather, differentiate directly into committed unipotent progenitors. SUMMARY: The diversity of transcriptional networks and metabolic pathways in HSCs and their downstream progeny allows a high level of plasticity in blood differentiation. The intricate interactions between these pathways, within the perivascular niche, broaden the specification of HSCs in pathological and stressed conditions

Metabolic regulation of hematopoietic stem cell commitment and erythroid differentiation

PURPOSE OF REVIEW: Hematopoietic stem cell (HSC) renewal and lineage differentiation are finely tuned processes, regulated by cytokines, transcription factors and cell-cell contacts. However, recent studies have shown that fuel utilization also conditions HSC fate. This review focuses on our current understanding of the metabolic pathways that govern HSC self-renewal, commitment and specification to the erythroid lineage. RECENT FINDINGS: HSCs reside in a hypoxic bone marrow niche that favors anaerobic glycolysis. Although this metabolic pathway is required for stem cell maintenance, other pathways also play critical roles. Fatty acid oxidation preserves HSC self-renewal by promoting asymmetric division, whereas oxidative phosphorylation induces lineage commitment. Committed erythroid progenitors support the production of 2.4 million erythrocytes per second in human adults via a synchronized regulation of iron, amino acid and glucose metabolism. Iron is indispensable for heme biosynthesis in erythroblasts; a process finely coordinated by at least two hormones, hepcidin and erythroferrone, together with multiple cell surface iron transporters. Furthermore, hemoglobin production is promoted by amino acid-induced mTOR signaling. Erythropoiesis is also strictly dependent on glutamine metabolism; under conditions where glutaminolysis is inhibited, erythropoietin-signaled progenitors are diverted to a myelomonocytic fate. Indeed, the utilization of both glutamine and glucose in de-novo nucleotide biosynthesis is a sine qua non for erythroid differentiation. SUMMARY: Diverse metabolic networks function in concert with transcriptional, translational and epigenetic programs to regulate HSC potential and orient physiological as well as pathological erythroid differentiation

Cell surface Glut1 levels distinguish human CD4 and CD8 T lymphocyte subsets with distinct effector functions

CD4 and CD8 T lymphocyte activation requires the generation of sufficient energy to support new biosynthetic demands. Following T cell receptor (TCR) engagement, these requirements are met by an increased glycolysis, due, at least in part, to induction of the Glut1 glucose transporter. As Glut1 is upregulated on tumor cells in response to hypoxia, we assessed whether surface Glut1 levels regulate the antigen responsiveness of human T lymphocytes in both hypoxic and atmospheric oxygen conditions. Notably, Glut1 upregulation in response to TCR stimulation was significantly higher in T lymphocytes activated under hypoxic as compared to atmospheric oxygen conditions. Furthermore, TCR-stimulated human T lymphocytes sorted on the basis of Glut1-Lo and Glut1-Hi profiles maintained distinct characteristics, irrespective of the oxygen tension. While T cells activated in hypoxia divided less than those activated in atmospheric oxygen, Glut1-Hi lymphocytes exhibited increased effector phenotype acquisition, augmented proliferation, and an inverted CD4/CD8 ratio in both oxygen conditions. Moreover, Glut1-Hi T lymphocytes exhibited a significantly enhanced ability to produce IFN-gamma and this secretion potential was completely dependent on continued glycolysis. Thus, Glut1 surface levels identify human T lymphocytes with distinct effector functions in both hypoxic and atmospheric oxygen tensions

Glutamine-dependent alpha-ketoglutarate production regulates the balance between T helper 1 cell and regulatory T cell generation

T cell activation requires that the cell meet increased energetic and biosynthetic demands. We showed that exogenous nutrient availability regulated the differentiation of naive CD4(+) T cells into distinct subsets. Activation of naive CD4(+) T cells under conditions of glutamine deprivation resulted in their differentiation into Foxp3(+) (forkhead box P3-positive) regulatory T (Treg) cells, which had suppressor function in vivo. Moreover, glutamine-deprived CD4(+) T cells that were activated in the presence of cytokines that normally induce the generation of T helper 1 (TH1) cells instead differentiated into Foxp3(+) Treg cells. We found that alpha-ketoglutarate (alphaKG), the glutamine-derived metabolite that enters into the mitochondrial citric acid cycle, acted as a metabolic regulator of CD4(+) T cell differentiation. Activation of glutamine-deprived naive CD4(+) T cells in the presence of a cell-permeable alphaKG analog increased the expression of the gene encoding the TH1 cell-associated transcription factor Tbet and resulted in their differentiation into TH1 cells, concomitant with stimulation of mammalian target of rapamycin complex 1 (mTORC1) signaling. Together, these data suggest that a decrease in the intracellular amount of alphaKG, caused by the limited availability of extracellular glutamine, shifts the balance between the generation of TH1 and Treg cells toward that of a Treg phenotype