MYC in Regulating Immunity: Metabolism and Beyond

Myelocytomatosis oncogene (MYC) family members, including cellular MYC (c-Myc), neuroblastoma derived MYC (MYCN), and lung carcinoma derived MYC (MYCL), have all been implicated as key oncogenic drivers in a broad range of human cancers. Beyond cancer, MYC plays an important role in other physiological and pathological processes, namely immunity and immunological diseases. MYC largely functions as a transcription factor that promotes the expression of numerous target genes to coordinate death, proliferation, and metabolism at the cellular, tissue, and organismal levels. It has been shown that the expression of MYC family members is tightly regulated in immune cells during development or upon immune stimulations. Emerging evidence suggests that MYC family members play essential roles in regulating the development, differentiation and activation of immune cells. Through driving the expression of a broad range of metabolic genes in immune cells, MYC family members coordinate metabolic programs to support immune functions. Here, we discuss our understanding of MYC biology in immune system and how modulation of MYC impacts immune metabolism and responses.

[1]  Thomas Korn,et al.  IL-17 and Th17 Cells. , 2009, Annual review of immunology.

[2]  G. Semenza,et al.  Oncogenic alterations of metabolism. , 1999, Trends in biochemical sciences.

[3]  D. Green,et al.  HIF1α–dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells , 2011, The Journal of experimental medicine.

[4]  Simon C. Potter,et al.  Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis , 2011, Nature.

[5]  Linda V. Sinclair,et al.  Single cell tuning of Myc expression by antigen receptor signal strength and interleukin-2 in T lymphocytes , 2015, The EMBO journal.

[6]  Ansuman T. Satpathy,et al.  IRF-8 extinguishes neutrophil production and promotes dendritic cell lineage commitment in both myeloid and lymphoid mouse progenitors. , 2012, Blood.

[7]  Vincent Frouin,et al.  A Myc-regulated transcriptional network controls B-cell fate in response to BCR triggering , 2009, BMC Genomics.

[8]  D. Green,et al.  The immune diet: meeting the metabolic demands of lymphocyte activation , 2012, F1000 biology reports.

[9]  B. Vennstrom,et al.  Isolation and characterization of c-myc, a cellular homolog of the oncogene (v-myc) of avian myelocytomatosis virus strain 29 , 1982, Journal of virology.

[10]  Carla Grandori,et al.  Modulation of T‐lymphocyte development, growth and cell size by the Myc antagonist and transcriptional repressor Mad1 , 2002, The EMBO journal.

[11]  M. Serrano,et al.  In Vivo Inhibition of c-MYC in Myeloid Cells Impairs Tumor-Associated Macrophage Maturation and Pro-Tumoral Activities , 2012, PloS one.

[12]  M. Ladanyi,et al.  Sporadic Amplification of the MYC Gene in Human Osteosarcomas , 1993, Diagnostic molecular pathology : the American journal of surgical pathology, part B.

[13]  D. Felsher,et al.  Reversible tumorigenesis by MYC in hematopoietic lineages. , 1999, Molecular cell.

[14]  D. Green,et al.  The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. , 2011, Immunity.

[15]  R. Steinman,et al.  Direct Type I IFN but Not MDA5/TLR3 Activation of Dendritic Cells Is Required for Maturation and Metabolic Shift to Glycolysis after Poly IC Stimulation , 2014, PLoS biology.

[16]  Jennifer Martinez,et al.  The relationship between metabolism and the autophagy machinery during the innate immune response. , 2013, Cell metabolism.

[17]  K. Frauwirth,et al.  Glutamine Uptake and Metabolism Are Coordinately Regulated by ERK/MAPK during T Lymphocyte Activation , 2010, The Journal of Immunology.

[18]  K. Kashiwagi,et al.  Modulation of cellular function by polyamines. , 2010, The international journal of biochemistry & cell biology.

[19]  T. Holowka,et al.  Toll-like receptor-induced changes in glycolytic metabolism regulate dendritic cell activation. , 2010, Blood.

[20]  D. Hardie,et al.  Regulation of the energy sensor AMP-activated protein kinase by antigen receptor and Ca2+ in T lymphocytes , 2006, The Journal of experimental medicine.

[21]  P. Vadiveloo.  Macrophages—proliferation, activation, and cell cycle proteins , 1999, Journal of leukocyte biology.

[22]  J. Rathmell,et al.  Metabolic pathways in T cell fate and function. , 2012, Trends in immunology.

[23]  Kathryn A. O’Donnell,et al.  The c-Myc target gene network. , 2006, Seminars in cancer biology.

[24]  J. Hamilton.  CSF‐1 and cell cycle control in macrophages , 1997, Molecular reproduction and development.

[25]  Charles Y. Lin,et al.  Transcriptional Amplification in Tumor Cells with Elevated c-Myc , 2012, Cell.

[26]  J. Rathmell,et al.  IL-7 promotes Glut1 trafficking and glucose uptake via STAT5-mediated activation of Akt to support T-cell survival. , 2008, Blood.

[27]  S. Biswas.  Metabolic Reprogramming of Immune Cells in Cancer Progression. , 2015, Immunity.

[28]  S. Gordon,et al.  Alternative activation of macrophages: an immunologic functional perspective. , 2009, Annual review of immunology.

[29]  D. Green,et al.  Activation‐induced cell death in T cells , 2003, Immunological reviews.

[30]  J L Cleveland,et al.  The ornithine decarboxylase gene is a transcriptional target of c-Myc. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[31]  E. Prochownik,et al.  MYC oncogenes and human neoplastic disease , 1999, Oncogene.

[32]  W. S. Hayward,et al.  Activation of a cellular onc gene by promoter insertion in ALV-induced lymphoid leukosis , 1981, Nature.

[33]  D. Green,et al.  T cell metabolism and the immune response. , 2012, Seminars in immunology.

[34]  M. Jenkins,et al.  Antigen presentation to naive CD4 T cells in the lymph node , 2003, Nature Immunology.

[35]  Greg M. Delgoffe,et al.  The mammalian target of rapamycin: linking T cell differentiation, function, and metabolism. , 2010, Immunity.

[36]  C. Martínez-A,et al.  c-Myc-deficient B lymphocytes are resistant to spontaneous and induced cell death , 2004, Cell Death and Differentiation.

[37]  J. Greenbaum,et al.  Selective inhibition of CD4+ T-cell cytokine production and autoimmunity by BET protein and c-Myc inhibitors , 2012, Proceedings of the National Academy of Sciences.

[38]  R. Eisenman,et al.  Two MAD tails: what the recent knockouts of Mad1 and Mxi1 tell us about the MYC/MAX/MAD network. , 1999, Biochimica et biophysica acta.

[39]  J. Rathmell,et al.  The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function. , 2014, Cell metabolism.

[40]  P. Vadiveloo,et al.  Lipopolysaccharide-induced cell cycle arrest in macrophages occurs independently of nitric oxide synthase II induction. , 2001, Biochimica et biophysica acta.

[41]  O. Lantz,et al.  The transcription factor PLZF directs the effector program of the NKT cell lineage. , 2008, Immunity.

[42]  H. Niiro,et al.  Decision making in the immune system: Regulation of B-cell fate by antigen-receptor signals , 2002, Nature Reviews Immunology.

[43]  F. Ginhoux,et al.  Monocytes and macrophages: developmental pathways and tissue homeostasis , 2014, Nature Reviews Immunology.

[44]  Chi V Dang,et al.  MYC on the Path to Cancer , 2012, Cell.

[45]  J. Rathmell,et al.  Glucose Uptake Is Limiting in T Cell Activation and Requires CD28-Mediated Akt-Dependent and Independent Pathways1 , 2008, The Journal of Immunology.

[46]  S. Akira,et al.  Pathogen Recognition and Innate Immunity , 2006, Cell.

[47]  G. Bishop,et al.  TRAF3 deficiency promotes metabolic reprogramming in B cells , 2016, Scientific Reports.

[48]  W. Paul,et al.  Peripheral CD4+ T‐cell differentiation regulated by networks of cytokines and transcription factors , 2010, Immunological reviews.

[49]  Antonio Lanzavecchia,et al.  Antigen-specific interaction between T and B cells , 1985, Nature.

[50]  Liang Zheng,et al.  Succinate is an inflammatory signal that induces IL-1β through HIF-1α , 2013, Nature.

[51]  L. Cantley,et al.  Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation , 2009, Science.

[52]  G. Evan,et al.  Role of c-MYC in alternative activation of human macrophages and tumor-associated macrophage biology. , 2012, Blood.

[53]  F. Alt,et al.  Transposition and amplification of oncogene-related sequences in human neuroblastomas , 1983, Cell.

[54]  D. Green,et al.  c-Myc Is a Universal Amplifier of Expressed Genes in Lymphocytes and Embryonic Stem Cells , 2012, Cell.

[55]  O. Warburg.  On the origin of cancer cells. , 1956, Science.

[56]  G. Evan,et al.  The c‐Myc protein induces cell cycle progression and apoptosis through dimerization with Max. , 1993, The EMBO journal.

[57]  R. Steinman,et al.  Dendritic cells and the control of immunity , 1998, Nature.

[58]  T. Wynn,et al.  Protective and pathogenic functions of macrophage subsets , 2011, Nature Reviews Immunology.

[59]  Alberto Mantovani,et al.  Orchestration of metabolism by macrophages. , 2012, Cell metabolism.

[60]  S. Shurtleff,et al.  Myc rescue of a mutant CSF-1 receptor impaired in mitogenic signalling , 1991, Nature.

[61]  J. Hall,et al.  The immediate effect of antigens on the cell output of a lymph node. , 1965, British journal of experimental pathology.

[62]  J. Rathmell,et al.  The metabolic life and times of a T‐cell , 2010, Immunological reviews.

[63]  C. Thompson,et al.  The CD28 signaling pathway regulates glucose metabolism. , 2002, Immunity.

[64]  L. O’Neill,et al.  Metabolic Reprograming in Macrophage Polarization , 2014, Front. Immunol..

[65]  Albert Bendelac,et al.  The biology of NKT cells. , 2007, Annual review of immunology.

[66]  D. Green,et al.  Metabolic Reprogramming Is Required for Antibody Production That Is Suppressed in Anergic but Exaggerated in Chronically BAFF-Exposed B Cells , 2014, The Journal of Immunology.

[67]  M. Groudine,et al.  Control of c-myc regulation in normal and neoplastic cells. , 1991, Advances in cancer research.

[68]  C. Mackay,et al.  T-cell function and migration. Two sides of the same coin. , 2000, The New England journal of medicine.

[69]  R. Eisenman,et al.  c-Myc enhances protein synthesis and cell size during B lymphocyte development. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[70]  Chih-Hao Chang,et al.  Fueling Immunity: Insights into Metabolism and Lymphocyte Function , 2013, Science.

[71]  Tsung-Cheng Chang,et al.  c-Myc suppression of miR-23 enhances mitochondrial glutaminase and glutamine metabolism , 2009, Nature.

[72]  R. Jaenisch,et al.  HIF-1α Is Essential for Myeloid Cell-Mediated Inflammation , 2003, Cell.

[73]  D. Littman,et al.  Plasticity of CD4+ T cell lineage differentiation. , 2009, Immunity.

[74]  A. Krueger,et al.  Articles on similar topics can be found in the following Blood collections Cell Cycle (231 articles) , 2006 .

[75]  H. Weiner,et al.  Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells , 2006, Nature.

[76]  S. Gordon,et al.  Alternative activation of macrophages: mechanism and functions. , 2010, Immunity.

[77]  R. Lidereau,et al.  Genetic alteration of the c-myc protooncogene (MYC) in human primary breast carcinomas. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[78]  D. Green,et al.  Proinflammatory signal suppresses proliferation and shifts macrophage metabolism from Myc-dependent to HIF1α-dependent , 2016, Proceedings of the National Academy of Sciences.

[79]  Julia Jellusova,et al.  The PI3K pathway in B cell metabolism , 2016, Critical reviews in biochemistry and molecular biology.

[80]  John L Cleveland,et al.  c-Myc is essential for vasculogenesis and angiogenesis during development and tumor progression. , 2002, Genes & development.

[81]  R. Eisenman,et al.  An overview of MYC and its interactome. , 2014, Cold Spring Harbor perspectives in medicine.

[82]  M. Nussenzweig,et al.  Origin and development of dendritic cells , 2010, Immunological reviews.

[83]  C. Thompson,et al.  IL-7 Enhances the Survival and Maintains the Size of Naive T Cells1 , 2001, The Journal of Immunology.

[84]  Russell G. Jones,et al.  Enhancing CD8 T-cell memory by modulating fatty acid metabolism , 2009, Nature.

[85]  R. Eisenman,et al.  Myc stimulates B lymphocyte differentiation and amplifies calcium signaling , 2007, The Journal of cell biology.

[86]  Ansuman T. Satpathy,et al.  L-Myc expression by dendritic cells is required for optimal T-cell priming , 2014, Nature.

[87]  D. Guertin,et al.  T cell exit from quiescence and differentiation into Th2 cells depend on Raptor-mTORC1-mediated metabolic reprogramming. , 2013, Immunity.

[88]  B. Crabtree,et al.  Glutamine metabolism in lymphocytes: its biochemical, physiological and clinical importance. , 1985, Quarterly journal of experimental physiology.

[89]  Hongbo Chi,et al.  Regulation and function of mTOR signalling in T cell fate decisions , 2012, Nature Reviews Immunology.

[90]  G. Semenza,et al.  Control of TH17/Treg Balance by Hypoxia-Inducible Factor 1 , 2011, Cell.

[91]  E. Laurenti,et al.  c-Myc controls the development of CD 8 TCR intestinal intraepithelial lymphocytes from thymic precursors by regulating IL-15 – dependent survival , 2010 .

[92]  Y. Urade,et al.  Immunosuppression via adenosine receptor activation by adenosine monophosphate released from apoptotic cells , 2014, eLife.

[93]  J. Rathmell,et al.  Cutting Edge: Distinct Glycolytic and Lipid Oxidative Metabolic Programs Are Essential for Effector and Regulatory CD4+ T Cell Subsets , 2011, The Journal of Immunology.

[94]  F. Gounari,et al.  Intrathymic proliferation wave essential for Vα14+ natural killer T cell development depends on c-Myc , 2009, Proceedings of the National Academy of Sciences.

[95]  P. Ward,et al.  Metabolic reprogramming: a cancer hallmark even warburg did not anticipate. , 2012, Cancer cell.

[96]  Stella Pelengaris,et al.  c-MYC: more than just a matter of life and death , 2002, Nature Reviews Cancer.

[97]  R. Eisenman,et al.  The Myc/Max/Mad network and the transcriptional control of cell behavior. , 2000, Annual review of cell and developmental biology.

[98]  S. Park,et al.  Mouse CD1-specific NK1 T cells: development, specificity, and function. , 1997, Annual review of immunology.

[99]  Jonathan D. G. Jones,et al.  The plant immune system , 2006, Nature.

[100]  Gerard I. Evan,et al.  Induction of apoptosis in fibroblasts by c-myc protein , 1992, Cell.

[101]  A. Regev,et al.  Dynamic regulatory network controlling Th17 cell differentiation , 2013, Nature.

[102]  A. Trumpp,et al.  Selective Requirement for c-Myc at an Early Stage of Vα14i NKT Cell Development 1 , 2009, The Journal of Immunology.

[103]  V. Nizet,et al.  HIF transcription factors, inflammation, and immunity. , 2014, Immunity.

[104]  S. Gordon,et al.  Monocyte and macrophage heterogeneity , 2005, Nature Reviews Immunology.

[105]  D. Green,et al.  Metabolic reprogramming and metabolic dependency in T cells , 2012, Immunological reviews.

[106]  T. Mak,et al.  Regulation of cancer cell metabolism , 2011, Nature Reviews Cancer.

[107]  H. Pehamberger,et al.  Influence of increased c-Myc expression on the growth characteristics of human melanoma. , 1999, The Journal of investigative dermatology.

[108]  S. Chiaretti,et al.  Genetic profile of T-cell acute lymphoblastic leukemias with MYC translocations. , 2014, Blood.

[109]  Chi V. Dang,et al.  c-Myc Target Genes Involved in Cell Growth, Apoptosis, and Metabolism , 1999, Molecular and Cellular Biology.

[110]  F. Alt,et al.  Analysis of C-MYC function in normal cells via conditional gene-targeted mutation. , 2001, Immunity.

[111]  A. Salmeron,et al.  BET bromodomain inhibition suppresses TH17-mediated pathology , 2013, The Journal of experimental medicine.

[112]  A. Strasser,et al.  B cell growth is controlled by phosphatidylinosotol 3-kinase-dependent induction of Rel/NF-kappaB regulated c-myc transcription. , 2002, Molecular cell.

[113]  M Schwab,et al.  Enhanced expression of the human gene N-myc consequent to amplification of DNA may contribute to malignant progression of neuroblastoma. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[114]  T. Chiles,et al.  Antigen receptor-mediated changes in glucose metabolism in B lymphocytes: role of phosphatidylinositol 3-kinase signaling in the glycolytic control of growth. , 2006, Blood.

[115]  C. June,et al.  Multiple mechanisms regulate c‐myc gene expression during normal T cell activation. , 1988, The EMBO journal.

[116]  Bruno Amati,et al.  Oncogenic activity of the c-Myc protein requires dimerization with Max , 1993, Cell.

[117]  B. Everts,et al.  Dendritic cell metabolism , 2014, Nature Reviews Immunology.

[118]  C. Dang.  MYC, metabolism, cell growth, and tumorigenesis. , 2013, Cold Spring Harbor perspectives in medicine.

[119]  G. Semenza,et al.  Differentiation Stage-Specific Requirement in Hypoxia-Inducible Factor-1α–Regulated Glycolytic Pathway during Murine B Cell Development in Bone Marrow , 2009, The Journal of Immunology.

[120]  O. Warburg.  [Origin of cancer cells]. , 1956, Oncologia.

[121]  D. Pellicci,et al.  A Natural Killer T (NKT) Cell Developmental Pathway Involving a Thymus-dependent NK1.1−CD4+ CD1d-dependent Precursor Stage , 2002, The Journal of experimental medicine.

[122]  F. Geissmann,et al.  Blood monocytes: development, heterogeneity, and relationship with dendritic cells. , 2009, Annual review of immunology.

[123]  A. Levine,et al.  Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function , 2010, Proceedings of the National Academy of Sciences.

[124]  Anthony Mancuso,et al.  Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction , 2008, Proceedings of the National Academy of Sciences.

[125]  J. Parkin,et al.  An overview of the immune system , 2001, The Lancet.

[126]  Teresa Palomero,et al.  A NOTCH1-driven MYC enhancer promotes T cell development, transformation and acute lymphoblastic leukemia , 2014, Nature Medicine.

[127]  Charles R. Evans,et al.  The Sedoheptulose Kinase CARKL Directs Macrophage Polarization through Control of Glucose Metabolism , 2012, Cell metabolism.

[128]  HIF1a–dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells , 2011 .

[129]  J. Edwards,et al.  Exploring the full spectrum of macrophage activation , 2008, Nature Reviews Immunology.

[130]  S. Gordon,et al.  Tissue macrophage heterogeneity: issues and prospects , 2013, Seminars in Immunopathology.

[131]  A Basten,et al.  An overview of the immune system. , 1991 .

[132]  Peter Tontonoz,et al.  Integration of metabolism and inflammation by lipid-activated nuclear receptors , 2008, Nature.

[133]  K. Zeller,et al.  Function of the c-Myc oncogenic transcription factor. , 1999, Experimental cell research.

[134]  S. Sugano,et al.  Phosphate-activated glutaminase (GLS2), a p53-inducible regulator of glutamine metabolism and reactive oxygen species , 2010, Proceedings of the National Academy of Sciences.

[135]  S. Gerondakis,et al.  The mitogen-induced increase in T cell size involves PKC and NFAT activation of Rel/NF-kappaB-dependent c-myc expression. , 2004, Immunity.

[136]  C Caux,et al.  Immunobiology of dendritic cells. , 2000, Annual review of immunology.

[137]  P. Worley,et al.  The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. , 2009, Immunity.

[138]  H. Wilson,et al.  Metabolism of activated T lymphocytes. , 2014, Current opinion in immunology.

[139]  L. O’Neill,et al.  Metabolic reprogramming in macrophages and dendritic cells in innate immunity , 2015, Cell Research.

[140]  P. Moschou,et al.  Polyamines and programmed cell death. , 2014, Journal of experimental botany.

[141]  R. Deberardinis,et al.  The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. , 2008, Cell metabolism.

[142]  T. Schumacher,et al.  Mapping the life histories of T cells , 2010, Nature Reviews Immunology.