Metabolic requirements for the maintenance of self-renewing stem cells (original) (raw)

• Weissman, I. L., Anderson, D. J. & Gage, F. Stem and progenitor cells: origins, phenotypes, lineage commitments, and transdifferentiations. Annu. Rev. Cell Dev. Biol. 17, 387–403 (2001).
  Article CAS PubMed Google Scholar
• Seita, J. & Weissman, I. L. Hematopoietic stem cell: self-renewal versus differentiation. Wiley Interdiscip. Rev. Syst. Biol. Med. 2, 640–653 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Zon, L. I. Intrinsic and extrinsic control of haematopoietic stem-cell self-renewal. Nature 453, 306–313 (2008).
  Article CAS PubMed Google Scholar
• He, S., Nakada, D. & Morrison, S. J. Mechanisms of stem cell self-renewal. Annu. Rev. Cell Dev. Biol. 25, 377–406 (2009).
  Article CAS PubMed Google Scholar
• van der Lugt, N. M. et al. Posterior transformation, neurological abnormalities, and severe hematopoietic defects in mice with a targeted deletion of the bmi-1 proto-oncogene. Genes Dev. 8, 757–769 (1994).
  Article CAS PubMed Google Scholar
• Morrison, S. J. & Kimble, J. Asymmetric and symmetric stem-cell divisions in development and cancer. Nature 441, 1068–1074 (2006).
  Article CAS PubMed Google Scholar
• Lansdorp, P. M. Intrinsic control of stem cell fate. Stem Cells 15 (Suppl. 1), 223–225; discussion 225–227 (1997).
  Article PubMed Google Scholar
• Suda, T., Suda, J. & Ogawa, M. Single-cell origin of mouse hemopoietic colonies expressing multiple lineages in variable combinations. Proc. Natl Acad. Sci. USA 80, 6689–6693 (1983).
  Article CAS PubMed PubMed Central Google Scholar
• Suda, T., Suda, J. & Ogawa, M. Disparate differentiation in mouse hemopoietic colonies derived from paired progenitors. Proc. Natl Acad. Sci. USA 81, 2520–2524 (1984).
  Article CAS PubMed PubMed Central Google Scholar
• Metcalf, D. Lineage commitment in the progeny of murine hematopoietic preprogenitor cells: influence of thrombopoietin and interleukin 5. Proc. Natl Acad. Sci. USA 95, 6408–6412 (1998).
  Article CAS PubMed PubMed Central Google Scholar
• Tothova, Z. & Gilliland, D. G. FoxO transcription factors and stem cell homeostasis: insights from the hematopoietic system. Cell Stem Cell 1, 140–152 (2007).
  Article CAS PubMed Google Scholar
• Ito, K. et al. Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells. Nature 431, 997–1002 (2004).
  Article CAS PubMed Google Scholar
• Ito, K. et al. Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells. Nature Med. 12, 446–451 (2006).
  Article CAS PubMed Google Scholar
• Miyamoto, K. et al. Foxo3a is essential for maintenance of the hematopoietic stem cell pool. Cell Stem Cell 1, 101–112 (2007).
  Article CAS PubMed Google Scholar
• Figueroa, M. E. et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18, 553–567 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Gan, B. et al. Lkb1 regulates quiescence and metabolic homeostasis of haematopoietic stem cells. Nature 468, 701–704 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Gurumurthy, S. et al. The Lkb1 metabolic sensor maintains haematopoietic stem cell survival. Nature 468, 659–663 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Nakada, D., Saunders, T. L. & Morrison, S. J. Lkb1 regulates cell cycle and energy metabolism in haematopoietic stem cells. Nature 468, 653–658 (2010). Together with references 16 and 17, this study demonstrates that the protein LKB1, which lies at the crossroad of energy metabolism and cell growth, seems to regulate HSC dynamics.
  Article CAS PubMed PubMed Central Google Scholar
• Tefferi, A. et al. IDH1 and IDH2 mutation studies in 1473 patients with chronic-, fibrotic- or blast-phase essential thrombocythemia, polycythemia vera or myelofibrosis. Leukemia 24, 1302–1309 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Ward, P. S. et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting α-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 17, 225–234 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Lu, C. et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483, 474–478 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Ito, K. et al. A PML–PPAR-δe pathway for fatty acid oxidation regulates hematopoietic stem cell maintenance. Nature Med. 18, 1350–1358 (2012). This study shows that PML acts as a critical rheostat responsible for fine-tuning tissue homeostasis.
  Article CAS PubMed Google Scholar
• Suda, T., Takubo, K. & Semenza, G. L. Metabolic regulation of hematopoietic stem cells in the hypoxic niche. Cell Stem Cell 9, 298–310 (2011). A comprehensive review on oxygen homeostasis, the hypoxic niche and energy metabolism for maintenance of HSC function and long-term self-renewal.
  Article CAS PubMed Google Scholar
• Orkin, S. H. & Zon, L. I. Hematopoiesis: an evolving paradigm for stem cell biology. Cell 132, 631–644 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Shyh-Chang, N., Daley, G. Q. & Cantley, L. C. Stem cell metabolism in tissue development and aging. Development 140, 2535–2547 (2013). An important review of recent studies of the balance among glycolysis, mitochondrial OXPHOS and oxidative stress in various forms of stem cells.
  Article CAS PubMed PubMed Central Google Scholar
• Xu, X. et al. Mitochondrial regulation in pluripotent stem cells. Cell. Metab. 18, 325–332 (2013).
  Article CAS PubMed Google Scholar
• Mohyeldin, A., Garzon-Muvdi, T. & Quinones-Hinojosa, A. Oxygen in stem cell biology: a critical component of the stem cell niche. Cell Stem Cell 7, 150–161 (2010).
  Article CAS PubMed Google Scholar
• Simon, M. C. & Keith, B. The role of oxygen availability in embryonic development and stem cell function. Nature Rev. Mol. Cell Biol. 9, 285–296 (2008).
  Article CAS Google Scholar
• Nombela-Arrieta, C. et al. Quantitative imaging of haematopoietic stem and progenitor cell localization and hypoxic status in the bone marrow microenvironment. Nature Cell Biol. 15, 533–543 (2013).
  Article CAS PubMed Google Scholar
• Simsek, T. et al. The distinct metabolic profile of hematopoietic stem cells reflects their location in a hypoxic niche. Cell Stem Cell 7, 380–390 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Suda, T. Hematopoiesis and bone remodeling. Blood 117, 5556–5557 (2011).
  Article CAS PubMed Google Scholar
• Takubo, K. et al. Regulation of glycolysis by Pdk functions as a metabolic checkpoint for cell cycle quiescence in hematopoietic stem cells. Cell Stem Cell 12, 49–61 (2013). This study demonstrates that glycolytic metabolic status governed by PDK acts as a cell cycle checkpoint that modulates HSC quiescence and function.
  Article CAS PubMed PubMed Central Google Scholar
• Warr, M. R. & Passegue, E. Metabolic makeover for HSCs. Cell Stem Cell 12, 1–3 (2013).
  Article CAS PubMed Google Scholar
• Yu, W. M. et al. Metabolic regulation by the mitochondrial phosphatase PTPMT1 is required for hematopoietic stem cell differentiation. Cell Stem Cell 12, 62–74 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Semenza, G. L. Oxygen homeostasis. Wiley Interdiscip Rev. Syst. Biol. Med. 2, 336–361 (2010).
  Article CAS PubMed Google Scholar
• Wang, G. L. & Semenza, G. L. Purification and characterization of hypoxia-inducible factor 1. J. Biol. Chem. 270, 1230–1237 (1995).
  Article CAS PubMed Google Scholar
• Wang, G. L., Jiang, B. H., Rue, E. A. & Semenza, G. L. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc. Natl Acad. Sci. USA 92, 5510–5514 (1995).
  Article CAS PubMed PubMed Central Google Scholar
• Cavadas, M. A., Nguyen, L. K. & Cheong, A. Hypoxia-inducible factor (HIF) network: insights from mathematical models. Cell Commun. Signal 11, 42 (2013).
  Article PubMed PubMed Central Google Scholar
• Nguyen, L. K. et al. A dynamic model of the hypoxia-inducible factor 1α (HIF-1α) network. J. Cell Sci. 126, 1454–1463 (2013).
  Article CAS PubMed Google Scholar
• Bruick, R. K. & McKnight, S. L. A conserved family of prolyl-4-hydroxylases that modify HIF. Science 294, 1337–1340 (2001).
  CAS PubMed Google Scholar
• Epstein, A. C. et al. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 107, 43–54 (2001).
  CAS PubMed Google Scholar
• Ivan, M. et al. Biochemical purification and pharmacological inhibition of a mammalian prolyl hydroxylase acting on hypoxia-inducible factor. Proc. Natl Acad. Sci. USA 99, 13459–13464 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Barger, J. F. & Plas, D. R. Balancing biosynthesis and bioenergetics: metabolic programs in oncogenesis. Endocr. Relat. Cancer 17, R287–304 (2010).
  Article CAS PubMed Google Scholar
• Semenza, G. L. Targeting HIF-1 for cancer therapy. Nature Rev. Cancer 3, 721–732 (2003).
  Article CAS Google Scholar
• Simon, M. C., Liu, L., Barnhart, B. C. & Young, R. M. Hypoxia-induced signaling in the cardiovascular system. Annu. Rev. Physiol. 70, 51–71 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Rouault-Pierre, K. et al. HIF-2α protects human hematopoietic stem/progenitors and acute myeloid leukemic cells from apoptosis induced by endoplasmic reticulum stress. Cell Stem Cell 13, 549–563 (2013).
  Article CAS PubMed Google Scholar
• Gu, Y. Z., Moran, S. M., Hogenesch, J. B., Wartman, L. & Bradfield, C. A. Molecular characterization and chromosomal localization of a third alpha-class hypoxia inducible factor subunit, HIF3α. Gene Expr 7, 205–213 (1998).
  CAS PubMed Google Scholar
• Makino, Y., Kanopka, A., Wilson, W. J., Tanaka, H. & Poellinger, L. Inhibitory PAS domain protein (IPAS) is a hypoxia-inducible splicing variant of the hypoxia-inducible factor-3α locus. J. Biol. Chem. 277, 32405–32408 (2002).
  CAS PubMed Google Scholar
• Kranc, K. R. et al. Cited2 is an essential regulator of adult hematopoietic stem cells. Cell Stem Cell 5, 659–665 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Du, J. et al. HIF-1α deletion partially rescues defects of hematopoietic stem cell quiescence caused by Cited2 deficiency. Blood 119, 2789–2798 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Du, J. et al. Cited2 is required for the maintenance of glycolytic metabolism in adult hematopoietic stem cells. Stem Cells Dev. 23, 83–94 (2014).
  Article CAS PubMed Google Scholar
• Miharada, K. et al. Cripto regulates hematopoietic stem cells as a hypoxic-niche-related factor through cell surface receptor GRP78. Cell Stem Cell 9, 330–344 (2011).
  Article CAS PubMed Google Scholar
• Miharada, K. et al. Hematopoietic stem cells are regulated by Cripto, as an intermediary of HIF-1αin the hypoxic bone marrow niche. Ann. NY Acad. Sci. 1266, 55–62 (2012).
  Article CAS PubMed Google Scholar
• Rossi, D. J., Jamieson, C. H. & Weissman, I. L. Stems cells and the pathways to aging and cancer. Cell 132, 681–696 (2008).
  Article CAS PubMed Google Scholar
• Chen, C. T., Shih, Y. R., Kuo, T. K., Lee, O. K. & Wei, Y. H. Coordinated changes of mitochondrial biogenesis and antioxidant enzymes during osteogenic differentiation of human mesenchymal stem cells. Stem Cells 26, 960–968 (2008).
  Article CAS PubMed Google Scholar
• Pattappa, G., Heywood, H. K., de Bruijn, J. D. & Lee, D. A. The metabolism of human mesenchymal stem cells during proliferation and differentiation. J. Cell. Physiol. 226, 2562–2570 (2011).
  Article CAS PubMed Google Scholar
• Pattappa, G. et al. Continuous and uninterrupted oxygen tension influences the colony formation and oxidative metabolism of human mesenchymal stem cells. Tissue Eng. Part C Methods 19, 68–79 (2013).
  Article CAS PubMed Google Scholar
• Renault, V. M. et al. FoxO3 regulates neural stem cell homeostasis. Cell Stem Cell 5, 527–539 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Van Blerkom, J. Mitochondria in early mammalian development. Semin. Cell Dev. Biol. 20, 354–364 (2009).
  Article CAS PubMed Google Scholar
• Kondoh, H. et al. A high glycolytic flux supports the proliferative potential of murine embryonic stem cells. Antioxid. Redox Signal 9, 293–299 (2007).
  Article CAS PubMed Google Scholar
• Shyh-Chang, N. et al. Influence of threonine metabolism on S-adenosylmethionine and histone methylation. Science 339, 222–226 (2013).
  Article CAS PubMed Google Scholar
• Folmes, C. D. et al. Somatic oxidative bioenergetics transitions into pluripotency-dependent glycolysis to facilitate nuclear reprogramming. Cell. Metab. 14, 264–271 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Varum, S. et al. Energy metabolism in human pluripotent stem cells and their differentiated counterparts. PLoS ONE 6, e20914 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Vander Heiden, M. G., Cantley, L. C. & Thompson, C. B. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324, 1029–1033 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Peng, S. et al. Genome-wide studies reveal that Lin28 enhances the translation of genes important for growth and survival of human embryonic stem cells. Stem Cells 29, 496–504 (2011).
  Article CAS PubMed Google Scholar
• Balzer, E. & Moss, E. G. Localization of the developmental timing regulator Lin28 to mRNP complexes, P-bodies and stress granules. RNA Biol. 4, 16–25 (2007).
  Article CAS PubMed Google Scholar
• Viswanathan, S. R., Daley, G. Q. & Gregory, R. I. Selective blockade of microRNA processing by Lin28. Science 320, 97–100 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Shyh-Chang, N. & Daley, G. Q. Lin28: primal regulator of growth and metabolism in stem cells. Cell Stem Cell 12, 395–406 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Yu, J. et al. Induced pluripotent stem cell lines derived from human somatic cells. Science 318, 1917–1920 (2007).
  Article CAS PubMed Google Scholar
• Yuan, J., Nguyen, C. K., Liu, X., Kanellopoulou, C. & Muljo, S. A. Lin28b reprograms adult bone marrow hematopoietic progenitors to mediate fetal-like lymphopoiesis. Science 335, 1195–1200 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Zheng, K., Wu, X., Kaestner, K. H. & Wang, P. J. The pluripotency factor LIN28 marks undifferentiated spermatogonia in mouse. BMC Dev. Biol. 9, 38 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Shyh-Chang, N. et al. Lin28 enhances tissue repair by reprogramming cellular metabolism. Cell 155, 778–792 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Zhu, H. et al. The Lin28/let-7 axis regulates glucose metabolism. Cell 147, 81–94 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Zhang, J. et al. UCP2 regulates energy metabolism and differentiation potential of human pluripotent stem cells. EMBO J. 30, 4860–4873 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Shyh-Chang, N., Zheng, Y., Locasale, J. W. & Cantley, L. C. Human pluripotent stem cells decouple respiration from energy production. EMBO J. 30, 4851–4852 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Forman, N. G. & Wilson, D. F. Energetics and stoichiometry of oxidative phosphorylation from NADH to cytochrome c in isolated rat liver mitochondria. J. Biol. Chem. 257, 12908–12915 (1982).
  CAS PubMed Google Scholar
• Wang, J. et al. Dependence of mouse embryonic stem cells on threonine catabolism. Science 325, 435–439 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Manganelli, G. et al. Modulation of the pentose phosphate pathway induces endodermal differentiation in embryonic stem cells. PLoS ONE 7, e29321 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Kathagen, A. et al. Hypoxia and oxygenation induce a metabolic switch between pentose phosphate pathway and glycolysis in glioma stem-like cells. Acta Neuropathol. 126, 763–80 (2013).
  Article CAS PubMed Google Scholar
• Zhao, F. et al. Imatinib resistance associated with BCR-ABL upregulation is dependent on HIF-1α-induced metabolic reprograming. Oncogene 29, 2962–2972 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Cho, Y. M. et al. Dynamic changes in mitochondrial biogenesis and antioxidant enzymes during the spontaneous differentiation of human embryonic stem cells. Biochem. Biophys. Res. Commun. 348, 1472–1478 (2006).
  Article CAS PubMed Google Scholar
• Chung, S., Arrell, D. K., Faustino, R. S., Terzic, A. & Dzeja, P. P. Glycolytic network restructuring integral to the energetics of embryonic stem cell cardiac differentiation. J. Mol. Cell Cardiol 48, 725–734 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Prigione, A., Fauler, B., Lurz, R., Lehrach, H. & Adjaye, J. The senescence-related mitochondrial/oxidative stress pathway is repressed in human induced pluripotent stem cells. Stem Cells 28, 721–733 (2010).
  Article CAS PubMed Google Scholar
• St John, J. C. et al. The expression of mitochondrial DNA transcription factors during early cardiomyocyte in vitro differentiation from human embryonic stem cells. Clon. Stem Cells 7, 141–153 (2005).
  Article CAS Google Scholar
• Norddahl, G. L. et al. Accumulating mitochondrial DNA mutations drive premature hematopoietic aging phenotypes distinct from physiological stem cell aging. Cell Stem Cell 8, 499–510 (2011).
  Article CAS PubMed Google Scholar
• Inoue, S. et al. Mitochondrial respiration defects modulate differentiation but not proliferation of hematopoietic stem and progenitor cells. FEBS Lett. 584, 3402–3409 (2010).
  Article CAS PubMed Google Scholar
• Maryanovich, M. et al. The ATM-BID pathway regulates quiescence and survival of haematopoietic stem cells. Nature Cell Biol. 14, 535–541 (2012).
  Article CAS PubMed Google Scholar
• Maryanovich, M. & Gross, A. A. ROS rheostat for cell fate regulation. Trends Cell Biol. 23, 129–134 (2013).
  Article CAS PubMed Google Scholar
• Weiss, C. N. & Ito, K. DNA damage response, redox status and hematopoiesis. Blood Cells Mol. Dis. 52, 12–18 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Tothova, Z. et al. FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell 128, 325–339 (2007). Together with references 11 and 14, this study demonstrates an important role of FOXO proteins in the maintenance and integrity of stem cells.
  Article CAS PubMed Google Scholar
• Paik, J. H. et al. FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis. Cell 128, 309–323 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Yamazaki, S. et al. Cytokine signals modulated via lipid rafts mimic niche signals and induce hibernation in hematopoietic stem cells. EMBO J. 25, 3515–3523 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Paik, J. H. et al. FoxOs cooperatively regulate diverse pathways governing neural stem cell homeostasis. Cell Stem Cell 5, 540–553 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Hagenbuchner, J. & Ausserlechner, M. J. Mitochondria and FOXO3: breath or die. Front. Physiol. 4, 147 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Mortensen, M. et al. The autophagy protein Atg7 is essential for hematopoietic stem cell maintenance. J. Exp. Med. 208, 455–467 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Warr, M. R. et al. FOXO3A directs a protective autophagy program in haematopoietic stem cells. Nature 494, 323–327 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Barzilai, A., Rotman, G. & Shiloh, Y. ATM deficiency and oxidative stress: a new dimension of defective response to DNA damage. DNA Repair 1, 3–25 (2002).
  Article CAS PubMed Google Scholar
• Allen, D. M. et al. Ataxia telangiectasia mutated is essential during adult neurogenesis. Genes Dev. 15, 554–566 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Jang, Y. Y. & Sharkis, S. J. A low level of reactive oxygen species selects for primitive hematopoietic stem cells that may reside in the low-oxygenic niche. Blood 110, 3056–3063 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Nitta, E. et al. Telomerase reverse transcriptase protects ATM-deficient hematopoietic stem cells from ROS-induced apoptosis through a telomere-independent mechanism. Blood 117, 4169–4180 (2011).
  Article CAS PubMed Google Scholar
• Kaplon, J. et al. A key role for mitochondrial gatekeeper pyruvate dehydrogenase in oncogene-induced senescence. Nature 498, 109–112 (2013).
  Article CAS PubMed Google Scholar
• Harris, J. M. et al. Glucose metabolism impacts the spatiotemporal onset and magnitude of HSC induction in vivo. Blood 121, 2483–2493 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Morimoto, H. et al. ROS are required for mouse spermatogonial stem cell self-renewal. Cell Stem Cell 12, 774–786 (2013).
  Article CAS PubMed Google Scholar
• Lewandowski, D. et al. In vivo cellular imaging pinpoints the role of reactive oxygen species in the early steps of adult hematopoietic reconstitution. Blood 115, 443–452 (2010).
  Article CAS PubMed Google Scholar
• Yuan, T. L. & Cantley, L. C. PI3K pathway alterations in cancer: variations on a theme. Oncogene 27, 5497–5510 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Kharas, M. G. & Gritsman, K. Akt: a double-edged sword for hematopoietic stem cells. Cell Cycle 9, 1223–1224 (2010).
  Article CAS PubMed Google Scholar
• Kharas, M. G. et al. Constitutively active AKT depletes hematopoietic stem cells and induces leukemia in mice. Blood 115, 1406–1415 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Yilmaz, O. H. et al. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature 441, 475–482 (2006).
  Article CAS PubMed Google Scholar
• Zhang, J. et al. PTEN maintains haematopoietic stem cells and acts in lineage choice and leukaemia prevention. Nature 441, 518–522 (2006).
  Article CAS PubMed Google Scholar
• Lee, J. Y. et al. mTOR activation induces tumor suppressors that inhibit leukemogenesis and deplete hematopoietic stem cells after Pten deletion. Cell Stem Cell 7, 593–605 (2010). In this study, mTOR activation depletes HSCs through a tumour suppressor response.
  Article CAS PubMed PubMed Central Google Scholar
• Chen, C. et al. TSC-mTOR maintains quiescence and function of hematopoietic stem cells by repressing mitochondrial biogenesis and reactive oxygen species. J. Exp. Med. 205, 2397–2408 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Gan, B. et al. mTORC1-dependent and -independent regulation of stem cell renewal, differentiation, and mobilization. Proc. Natl Acad. Sci. USA 105, 19384–19389 (2008).
  Article PubMed PubMed Central Google Scholar
• Groszer, M. et al. Negative regulation of neural stem/progenitor cell proliferation by the Pten tumor suppressor gene in vivo. Science 294, 2186–2189 (2001).
  Article CAS PubMed Google Scholar
• Zhou, J. et al. Tsc1 mutant neural stem/progenitor cells exhibit migration deficits and give rise to subependymal lesions in the lateral ventricle. Genes Dev. 25, 1595–1600 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Yilmaz, O. H. et al. mTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake. Nature 486, 490–495 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Shackelford, D. B. & Shaw, R. J. The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nature Rev. Cancer 9, 563–575 (2009).
  Article CAS Google Scholar
• Hsu, P. P. & Sabatini, D. M. Cancer cell metabolism: Warburg and beyond. Cell 134, 703–707 (2008).
  Article CAS PubMed Google Scholar
• Wise, D. R. & Thompson, C. B. Glutamine addiction: a new therapeutic target in cancer. Trends Biochem. Sci. 35, 427–433 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Son, J. et al. Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature 496, 101–105 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Dang, C. V. et al. The c-Myc target gene network. Semin. Cancer Biol. 16, 253–264 (2006).
  Article CAS PubMed Google Scholar
• Carracedo, A. et al. A metabolic prosurvival role for PML in breast cancer. J. Clin. Invest. 122, 3088–3100 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Carracedo, A., Cantley, L. C. & Pandolfi, P. P. Cancer metabolism: fatty acid oxidation in the limelight. Nature Rev. Cancer 13, 227–232 (2013).
  Article CAS Google Scholar
• Schafer, Z. T. et al. Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment. Nature 461, 109–113 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Dunning, K. R. et al. Beta-oxidation is essential for mouse oocyte developmental competence and early embryo development. Biol. Reprod. 83, 909–918 (2010).
  Article CAS PubMed Google Scholar
• Zaugg, K. et al. Carnitine palmitoyltransferase 1C promotes cell survival and tumor growth under conditions of metabolic stress. Genes Dev. 25, 1041–1051 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Ito, K. et al. PML targeting eradicates quiescent leukaemia-initiating cells. Nature 453, 1072–1078 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Kiel, M. J. et al. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell 121, 1109–1121 (2005).
  Article CAS PubMed Google Scholar
• Arai, F. et al. Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell 118, 149–161 (2004).
  Article CAS PubMed Google Scholar
• Ito, K. & Ito, K. Newly Identified Roles of PML in Stem Cell Biology. Front. Oncol. 3, 50 (2013).
  Article PubMed PubMed Central Google Scholar
• Riserus, U. et al. Activation of peroxisome proliferator-activated receptor (PPAR) δ promotes reversal of multiple metabolic abnormalities, reduces oxidative stress, and increases fatty acid oxidation in moderately obese men. Diabetes 57, 332–339 (2008).
  Article CAS PubMed Google Scholar
• Berger, J. P., Akiyama, T. E. & Meinke, P. T. PPARs: therapeutic targets for metabolic disease. Trends Pharmacol. Sci. 26, 244–251 (2005).
  Article CAS PubMed Google Scholar
• Wagner, K. D. & Wagner, N. Peroxisome proliferator-activated receptor beta/delta (PPARβ/δ) acts as regulator of metabolism linked to multiple cellular functions. Pharmacol. Ther. 125, 423–435 (2010).
  Article CAS PubMed Google Scholar
• Samudio, I. et al. Pharmacologic inhibition of fatty acid oxidation sensitizes human leukemia cells to apoptosis induction. J. Clin. Invest. 120, 142–156 (2010).
  Article CAS PubMed Google Scholar
• Hosokawa, K. et al. Function of oxidative stress in the regulation of hematopoietic stem cell-niche interaction. Biochem. Biophys. Res. Commun. 363, 578–583 (2007).
  Article CAS PubMed Google Scholar
• Pike, L. S., Smift, A. L., Croteau, N. J., Ferrick, D. A. & Wu, M. Inhibition of fatty acid oxidation by etomoxir impairs NADPH production and increases reactive oxygen species resulting in ATP depletion and cell death in human glioblastoma cells. Biochim. Biophys. Acta 1807, 726–734 (2011).
  Article CAS PubMed Google Scholar
• Jeon, S. M., Chandel, N. S. & Hay, N. AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress. Nature 485, 661–665 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Caro, P. et al. Metabolic signatures uncover distinct targets in molecular subsets of diffuse large B cell lymphoma. Cancer Cell 22, 547–560 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Knobloch, M. et al. Metabolic control of adult neural stem cell activity by Fasn-dependent lipogenesis. Nature 493, 226–230 (2013).
  Article CAS PubMed Google Scholar
• Galdieri, L. & Vancura, A. Acetyl-CoA carboxylase regulates global histone acetylation. J. Biol. Chem. 287, 23865–23876 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Lerit, D. A., Smyth, J. T. & Rusan, N. M. Organelle asymmetry for proper fitness, function, and fate. Chromosome Res. 21, 271–286 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Filosa, S. et al. Failure to increase glucose consumption through the pentose-phosphate pathway results in the death of glucose-6-phosphate dehydrogenase gene-deleted mouse embryonic stem cells subjected to oxidative stress. Biochem. J. 370, 935–943 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Christofk, H. R. et al. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature 452, 230–233 (2008).
  Article CAS PubMed Google Scholar
• Israelsen, W. J. et al. PKM2 isoform-specific deletion reveals a differential requirement for pyruvate kinase in tumor cells. Cell 155, 397–409 (2013).
  Article CAS PubMed Google Scholar
• Anastasiou, D. et al. Inhibition of pyruvate kinase M2 by reactive oxygen species contributes to cellular antioxidant responses. Science 334, 1278–1283 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Shih, A. H., Abdel-Wahab, O., Patel, J. P. & Levine, R. L. The role of mutations in epigenetic regulators in myeloid malignancies. Nature Rev. Cancer 12, 599–612 (2012).
  Article CAS Google Scholar
• Jones, P. A. & Baylin, S. B. The fundamental role of epigenetic events in cancer. Nature Rev. Genet. 3, 415–428 (2002).
  Article CAS PubMed Google Scholar
• Viswanathan, S. R. & Daley, G. Q. Lin28: A microRNA regulator with a macro role. Cell 140, 445–449 (2010).
  Article CAS PubMed Google Scholar
• Song, S. J. et al. MicroRNA-antagonism regulates breast cancer stemness and metastasis via tet-family-dependent chromatin remodeling. Cell 154, 311–324 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Song, S. J. et al. The oncogenic microRNA miR-22 targets the TET2 tumor suppressor to promote hematopoietic stem cell self-renewal and transformation. Cell Stem Cell 13, 87–101 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Zhu, H. et al. Lin28a transgenic mice manifest size and puberty phenotypes identified in human genetic association studies. Nature Genet. 42, 626–630 (2010).
  Article CAS PubMed Google Scholar
• Reya, T., Morrison, S. J., Clarke, M. F. & Weissman, I. L. Stem cells, cancer, and cancer stem cells. Nature 414, 105–111 (2001).
  Article CAS PubMed Google Scholar
• Visvader, J. E. & Lindeman, G. J. Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nature Rev. Cancer 8, 755–768 (2008).
  Article CAS Google Scholar
• Dalerba, P., Cho, R. W. & Clarke, M. F. Cancer stem cells: models and concepts. Annu. Rev. Med. 58, 267–284 (2007).
  Article CAS PubMed Google Scholar
• Huntly, B. J. & Gilliland, D. G. Leukaemia stem cells and the evolution of cancer-stem-cell research. Nature Rev. Cancer 5, 311–321 (2005).
  Article CAS Google Scholar
• Wang, J. C. & Dick, J. E. Cancer stem cells: lessons from leukemia. Trends Cell Biol. 15, 494–501 (2005).
  Article CAS PubMed Google Scholar
• Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).
  CAS PubMed Google Scholar
• Sen Banerjee, S. et al. HIF-prolyl hydroxylases and cardiovascular diseases. Toxicol. Mech. Methods 22, 347–358 (2012).
  Article CAS PubMed Google Scholar
• Steinhauser, M. L. et al. Multi-isotope imaging mass spectrometry quantifies stem cell division and metabolism. Nature 481, 516–519 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Qu, W. et al. Synthesis of optically pure 4-fluoro-glutamines as potential metabolic imaging agents for tumors. J. Am. Chem. Soc. 133, 1122–1133 (2011).
  Article CAS PubMed Google Scholar
• Hosokawa, K. et al. Cadherin-based adhesion is a potential target for niche manipulation to protect hematopoietic stem cells in adult bone marrow. Cell Stem Cell 6, 194–198 (2010).
  Article CAS PubMed Google Scholar
• Parsons, D. W. et al. An integrated genomic analysis of human glioblastoma multiforme. Science 321, 1807–1812 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Mardis, E. R. et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N. Engl. J. Med. 361, 1058–1066 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Wise, D. R. et al. Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of α-ketoglutarate to citrate to support cell growth and viability. Proc. Natl Acad. Sci. USA 108, 19611–19616 (2011).
  Article PubMed PubMed Central Google Scholar
• Sasaki, M. et al. IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics. Nature 488, 656–659 (2012). Important report that demonstrates mechanistic links between an Idh1 mutation, human acute myeloid leukaemia and the induction of a leukaemic DNA methylation signature in a mouse model.
  Article CAS PubMed PubMed Central Google Scholar
• Kats, L. M. et al. Proto-oncogenic role of mutant idh2 in leukemia initiation and maintenance. Cell Stem Cell http://dx.doi.org/10.1016/j.stem.2013.12.016 (2014).
• Cimmino, L., Abdel-Wahab, O., Levine, R. L. & Aifantis, I. TET family proteins and their role in stem cell differentiation and transformation. Cell Stem Cell 9, 193–204 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Yan, H. et al. IDH1 and IDH2 mutations in gliomas. N. Engl. J. Med. 360, 765–773 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Dang, L., Jin, S. & Su, S. M. IDH mutations in glioma and acute myeloid leukemia. Trends Mol. Med. 16, 387–397 (2010).
  Article CAS PubMed Google Scholar
• Yang, H., Ye, D., Guan, K. L. & Xiong, Y. IDH1 and IDH2 mutations in tumorigenesis: mechanistic insights and clinical perspectives. Clin. Cancer Res. 18, 5562–5571 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Zhao, S. et al. Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1α. Science 324, 261–265 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Christensen, B. C. et al. DNA methylation, isocitrate dehydrogenase mutation, and survival in glioma. J. Natl Cancer Inst. 103, 143–153 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Murugan, A. K., Bojdani, E. & Xing, M. Identification and functional characterization of isocitrate dehydrogenase 1 (IDH1) mutations in thyroid cancer. Biochem. Biophys. Res. Commun. 393, 555–559 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Amary, M. F. et al. Ollier disease and Maffucci syndrome are caused by somatic mosaic mutations of IDH1 and IDH2. Nature Genet. 43, 1262–1265 (2011).
  Article CAS PubMed Google Scholar
• Pansuriya, T. C. et al. Somatic mosaic IDH1 and IDH2 mutations are associated with enchondroma and spindle cell hemangioma in Ollier disease and Maffucci syndrome. Nature Genet. 43, 1256–1261 (2011).
  Article CAS PubMed Google Scholar
• Borger, D. R. et al. Frequent mutation of isocitrate dehydrogenase (IDH)1 and IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping. Oncologist 17, 72–79 (2012).
  Article CAS PubMed Google Scholar
• Wang, P. et al. Mutations in isocitrate dehydrogenase 1 and 2 occur frequently in intrahepatic cholangiocarcinomas and share hypermethylation targets with glioblastomas. Oncogene 32, 3091–3100 (2013).
  Article CAS PubMed Google Scholar
• Gottlob, K. et al. Inhibition of early apoptotic events by Akt/PKB is dependent on the first committed step of glycolysis and mitochondrial hexokinase. Genes Dev. 15, 1406–1418 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Plas, D. R., Talapatra, S., Edinger, A. L., Rathmell, J. C. & Thompson, C. B. Akt and Bcl-xL promote growth factor-independent survival through distinct effects on mitochondrial physiology. J. Biol. Chem. 276, 12041–12048 (2001).
  Article CAS PubMed Google Scholar
• Yuneva, M., Zamboni, N., Oefner, P., Sachidanandam, R. & Lazebnik, Y. Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells. J. Cell Biol. 178, 93–105 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Brunelle, J. K. et al. c-Myc sensitization to oxygen deprivation-induced cell death is dependent on Bax/Bak, but is independent of p53 and hypoxia-inducible factor-1. J. Biol. Chem. 279, 4305–4312 (2004).
  Article CAS PubMed Google Scholar
• Wise, D. R. et al. Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc. Natl Acad. Sci. USA 105, 18782–18787 (2008).
  Article PubMed PubMed Central Google Scholar
• Gao, P. et al. c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature 458, 762–765 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Wilson, A. et al. c-Myc controls the balance between hematopoietic stem cell self-renewal and differentiation. Genes Dev. 18, 2747–2763 (2004). Demonstrates that MYC controls the balance between HSC self-renewal and differentiation.
  Article CAS PubMed PubMed Central Google Scholar
• Laurenti, E., Wilson, A. & Trumpp, A. Myc's other life: stem cells and beyond. Curr. Opin. Cell Biol. 21, 844–854 (2009).
  Article CAS PubMed Google Scholar
• Spencer, J.A. et al. Direct measurement of local oxygen concentration in the bone marrow of live animals. Nature http://dx.doi.org/10.1038/nature13034 (2014).