1932

Abstract

Unlike other cell types, B cells undergo multiple rounds of V(D)J recombination and hypermutation to evolve high-affinity antibodies. Reflecting high frequencies of DNA double-strand breaks, adaptive immune protection by B cells comes with an increased risk of malignant transformation. In addition, the vast majority of newly generated B cells express an autoreactive B cell receptor (BCR). Thus, B cells are under intense selective pressure to remove autoreactive and premalignant clones. Despite stringent negative selection, B cells frequently give rise to autoimmune disease and B cell malignancies. In this review, we discuss mechanisms that we term metabolic gatekeepers to eliminate pathogenic B cell clones on the basis of energy depletion. Chronic activation signals from autoreactive BCRs or transforming oncogenes increase energy demands in autoreactive and premalignant B cells. Thus, metabolic gatekeepers limit energy supply to levels that are insufficient to fuel either a transforming oncogene or hyperactive signaling from an autoreactive BCR.

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2021-01-24
2024-06-13
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Literature Cited

  1. 1. 
    Rajewsky K. 1996. Clonal selection and learning in the antibody system. Nature 381:751–58
    [Google Scholar]
  2. 2. 
    Swaminathan S, Klemm L, Park E, Papaemmanuil E, Ford A et al. 2015. Mechanisms of clonal evolution in childhood acute lymphoblastic leukemia. Nat. Immunol. 16:766–74
    [Google Scholar]
  3. 3. 
    Wardemann H, Yurasov S, Schaefer A, Young JW, Meffre E, Nussenzweig MC 2003. Predominant autoantibody production by early human B cell precursors. Science 301:1374–77
    [Google Scholar]
  4. 4. 
    Müschen M. 2019. Metabolic gatekeepers to safeguard against autoimmunity and oncogenic B cell transformation. Nat. Rev. Immunol. 19:337–48
    [Google Scholar]
  5. 5. 
    Lam KP, Kuhn R, Rajewsky K 1997. In vivo ablation of surface immunoglobulin on mature B cells by inducible gene targeting results in rapid cell death. Cell 90:1073–83
    [Google Scholar]
  6. 6. 
    MacLennan IC. 1995. Autoimmunity. Deletion of autoreactive B cells. Curr. Biol. 5:103–6
    [Google Scholar]
  7. 7. 
    Osmond DG. 1991. Proliferation kinetics and the lifespan of B cells in central and peripheral lymphoid organs. Curr. Opin. Immunol. 3:179–85
    [Google Scholar]
  8. 8. 
    Limnander A, Depeille P, Freedman TS, Liou J, Leitges M et al. 2011. STIM1, PKC-δ and RasGRP set a threshold for proapoptotic Erk signaling during B cell development. Nat. Immunol. 12:425–33
    [Google Scholar]
  9. 9. 
    Müschen M. 2018. Autoimmunity checkpoints as therapeutic targets in B cell malignancies. Nat. Rev. Cancer 18:103–16
    [Google Scholar]
  10. 10. 
    Young RM, Phelan JD, Wilson WH, Staudt LM 2019. Pathogenic B-cell receptor signaling in lymphoid malignancies: new insights to improve treatment. Immunol. Rev. 291:190–213
    [Google Scholar]
  11. 11. 
    Feldhahn N, Klein F, Mooster JL, Hadweh P, Sprangers M et al. 2005. Mimicry of a constitutively active pre–B cell receptor in acute lymphoblastic leukemia cells. J. Exp. Med. 201:1837–52
    [Google Scholar]
  12. 12. 
    Chan LN, Chen Z, Braas D, Lee JW, Xiao G et al. 2017. Metabolic gatekeeper function of B-lymphoid transcription factors. Nature 542:479–83
    [Google Scholar]
  13. 13. 
    Robin ED, Wong R. 1988. Mitochondrial DNA molecules and virtual number of mitochondria per cell in mammalian cells. J. Cell Physiol. 136:507–13
    [Google Scholar]
  14. 14. 
    Waters LR, Ahsan FM, Wolf DM, Shirihai O, Teitell MA 2018. Initial B cell activation induces metabolic reprogramming and mitochondrial remodeling. iScience 5:99–109
    [Google Scholar]
  15. 15. 
    Martinez-Martin N, Maldonado P, Gasparrini F, Frederico B, Aggarwal S et al. 2017. A switch from canonical to noncanonical autophagy shapes B cell responses. Science 355:641–47
    [Google Scholar]
  16. 16. 
    Westermann B. 2010. Mitochondrial fusion and fission in cell life and death. Nat. Rev. Mol. Cell Biol. 11:872–84
    [Google Scholar]
  17. 17. 
    Pickles S, Vigie P, Youle RJ 2018. Mitophagy and quality control mechanisms in mitochondrial maintenance. Curr. Biol. 28:R170–85
    [Google Scholar]
  18. 18. 
    Jang KJ, Mano H, Aoki K, Hayashi T, Muto A et al. 2015. Mitochondrial function provides instructive signals for activation-induced B-cell fates. Nat. Commun. 6:6750
    [Google Scholar]
  19. 19. 
    Adams WC, Chen YH, Kratchmarov R, Yen B, Nish SA et al. 2016. Anabolism-associated mitochondrial stasis driving lymphocyte differentiation over self-renewal. Cell Rep 17:3142–52
    [Google Scholar]
  20. 20. 
    Ng SY, Yoshida T, Zhang J, Georgopoulos K 2009. Genome-wide lineage-specific transcriptional networks underscore Ikaros-dependent lymphoid priming in hematopoietic stem cells. Immunity 30:493–507
    [Google Scholar]
  21. 21. 
    Pongubala JM, Northrup DL, Lancki DW, Medina KL, Treiber T et al. 2008. Transcription factor EBF restricts alternative lineage options and promotes B cell fate commitment independently of Pax5. Nat. Immunol. 9:203–15
    [Google Scholar]
  22. 22. 
    Nutt SL, Heavey B, Rolink AG, Busslinger M 1999. Commitment to the B-lymphoid lineage depends on the transcription factor Pax5. Nature 401:556–62
    [Google Scholar]
  23. 23. 
    Mullighan CG, Su X, Zhang J, Radtke I, Phillips LA et al. 2009. Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N. Engl. J. Med. 360:470–80
    [Google Scholar]
  24. 24. 
    Mullighan CG, Miller CB, Radtke I, Phillips LA, Dalton J et al. 2008. BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros. Nature 453:110–14
    [Google Scholar]
  25. 25. 
    Xie H, Ye M, Feng R, Graf T 2004. Stepwise reprogramming of B cells into macrophages. Cell 117:663–76
    [Google Scholar]
  26. 26. 
    Fretz JA, Nelson T, Xi Y, Adams DJ, Rosen CJ, Horowitz MC 2010. Altered metabolism and lipodystrophy in the early B-cell factor 1–deficient mouse. Endocrinology 151:1611–21
    [Google Scholar]
  27. 27. 
    Brennan-Speranza TC, Henneicke H, Gasparini SJ, Blankenstein KI, Heinevetter U et al. 2012. Osteoblasts mediate the adverse effects of glucocorticoids on fuel metabolism. J. Clin. Investig. 122:4172–89
    [Google Scholar]
  28. 28. 
    Wu N, Zheng B, Shaywitz A, Dagon Y, Tower C et al. 2013. AMPK-dependent degradation of TXNIP upon energy stress leads to enhanced glucose uptake via GLUT1. Mol. Cell 49:1167–75
    [Google Scholar]
  29. 29. 
    Martín-Lorenzo A, Auer F, Chan LN, García-Ramírez I, González-Herrero I et al. 2018. Loss of Pax5 exploits Sca1-BCR-ABLp190 susceptibility to confer the metabolic shift essential for pB-ALL. Cancer Res 78:2669–79
    [Google Scholar]
  30. 30. 
    Shojaee S, Chan LN, Buchner M, Cazzaniga V, Cosgun KN et al. 2016. PTEN opposes negative selection and enables oncogenic transformation of pre-B cells. Nat. Med. 22:379–87
    [Google Scholar]
  31. 31. 
    Schwickert TA, Tagoh H, Schindler K, Fischer M, Jaritz M, Busslinger M 2019. Ikaros prevents autoimmunity by controlling anergy and Toll-like receptor signaling in B cells. Nat. Immunol. 20:1517–29
    [Google Scholar]
  32. 32. 
    Wojcik H, Griffiths E, Staggs S, Hagman J, Winandy S 2007. Expression of a non-DNA-binding Ikaros isoform exclusively in B cells leads to autoimmunity but not leukemogenesis. Eur. J. Immunol. 37:1022–32
    [Google Scholar]
  33. 33. 
    Cazzaniga G, van Delft FW, Lo Nigro L, Ford AM, Score J et al. 2011. Developmental origins and impact of BCR-ABL1 fusion and IKZF1 deletions in monozygotic twins with Ph+ acute lymphoblastic leukemia. Blood 118:5559–64
    [Google Scholar]
  34. 34. 
    Gale KB, Ford AM, Repp R, Borkhardt A, Keller C et al. 1997. Backtracking leukemia to birth: identification of clonotypic gene fusion sequences in neonatal blood spots. PNAS 94:13950–54
    [Google Scholar]
  35. 35. 
    Wiemels JL, Cazzaniga G, Daniotti M, Eden OB, Addison GM et al. 1999. Prenatal origin of acute lymphoblastic leukaemia in children. Lancet 354:1499–503
    [Google Scholar]
  36. 36. 
    Biernaux C, Loos M, Sels A, Huez G, Stryckmans P 1995. Detection of major bcr-abl gene expression at a very low level in blood cells of some healthy individuals. Blood 86:3118–22
    [Google Scholar]
  37. 37. 
    Takagi M, Shinoda K, Piao J, Mitsuiki N, Takagi M et al. 2011. Autoimmune lymphoproliferative syndrome–like disease with somatic KRAS mutation. Blood 117:2887–90
    [Google Scholar]
  38. 38. 
    Hench PS, Slocumb CH et al. 1949. The effects of the adrenal cortical hormone 17-hydroxy-11-dehydrocorticosterone (Compound E) on the acute phase of rheumatic fever: preliminary report. Proc. Staff Meet. Mayo Clin. 24:277–97
    [Google Scholar]
  39. 39. 
    Ward LE, Slocumb CH, Polley HF, Lowman EW, Hench PS 1951. Clinical effects of cortisone administered orally to patients with rheumatoid arthritis. Proc. Staff Meet. Mayo Clin. 26:361–70
    [Google Scholar]
  40. 40. 
    Pearson OH, Eliel LP, Rawson RW, Dobriner K, Rhoads CP 1949. Adrenocorticotropic hormone- and cortisone-induced regression of lymphoid tumors in man. A preliminary report. Cancer 2:943–45
    [Google Scholar]
  41. 41. 
    Kaspers GJ, Kardos G, Pieters R, Van Zantwijk CH, Klumper E et al. 1994. Different cellular drug resistance profiles in childhood lymphoblastic and non-lymphoblastic leukemia: a preliminary report. Leukemia 8:1224–29
    [Google Scholar]
  42. 42. 
    Biddinger SB, Kahn CR. 2006. From mice to men: insights into the insulin resistance syndromes. Annu. Rev. Physiol. 68:123–58
    [Google Scholar]
  43. 43. 
    Piovan E, Yu J, Tosello V, Herranz D, Ambesi-Impiombato A et al. 2013. Direct reversal of glucocorticoid resistance by AKT inhibition in acute lymphoblastic leukemia. Cancer Cell 24:766–76
    [Google Scholar]
  44. 44. 
    Marke R, Havinga J, Cloos J, Demkes M, Poelmans G et al. 2016. Tumor suppressor IKZF1 mediates glucocorticoid resistance in B-cell precursor acute lymphoblastic leukemia. Leukemia 30:1599–603
    [Google Scholar]
  45. 45. 
    Pui CH, Evans WE. 2006. Treatment of acute lymphoblastic leukemia. N. Engl. J. Med. 354:166–78
    [Google Scholar]
  46. 46. 
    Holleman A, Cheok MH, den Boer ML, Yang W, Veerman AJ et al. 2004. Gene-expression patterns in drug-resistant acute lymphoblastic leukemia cells and response to treatment. N. Engl. J. Med. 351:533–42
    [Google Scholar]
  47. 47. 
    Pearce EL, Pearce EJ. 2013. Metabolic pathways in immune cell activation and quiescence. Immunity 38:633–43
    [Google Scholar]
  48. 48. 
    Lin WH, Adams WC, Nish SA, Chen YH, Yen B et al. 2015. Asymmetric PI3K signaling driving developmental and regenerative cell fate bifurcation. Cell Rep 13:2203–18
    [Google Scholar]
  49. 49. 
    Klein U, Casola S, Cattoretti G, Shen Q, Lia M et al. 2006. Transcription factor IRF4 controls plasma cell differentiation and class-switch recombination. Nat. Immunol. 7:773–82
    [Google Scholar]
  50. 50. 
    Shi W, Liao Y, Willis SN, Taubenheim N, Inouye M et al. 2015. Transcriptional profiling of mouse B cell terminal differentiation defines a signature for antibody-secreting plasma cells. Nat. Immunol. 16:663–73
    [Google Scholar]
  51. 51. 
    Lin YC, Jhunjhunwala S, Benner C, Heinz S, Welinder E et al. 2010. A global network of transcription factors, involving E2A, EBF1 and Foxo1, that orchestrates B cell fate. Nat. Immunol. 11:635–43
    [Google Scholar]
  52. 52. 
    Sander S, Chu VT, Yasuda T, Franklin A, Graf R et al. 2015. PI3 kinase and FOXO1 transcription factor activity differentially control B cells in the germinal center light and dark zones. Immunity 43:1075–86
    [Google Scholar]
  53. 53. 
    Shaffer AL, Emre NC, Lamy L, Ngo VN, Wright G et al. 2008. IRF4 addiction in multiple myeloma. Nature 454:226–31
    [Google Scholar]
  54. 54. 
    Wilhelm K, Happel K, Eelen G, Schoors S, Oellerich MF et al. 2016. FOXO1 couples metabolic activity and growth state in the vascular endothelium. Nature 529:216–20
    [Google Scholar]
  55. 55. 
    Liu Y, Dentin R, Chen D, Hedrick S, Ravnskjaer K et al. 2008. A fasting inducible switch modulates gluconeogenesis via activator/coactivator exchange. Nature 456:269–73
    [Google Scholar]
  56. 56. 
    Schebesta A, McManus S, Salvagiotto G, Delogu A, Busslinger GA, Busslinger M 2007. Transcription factor Pax5 activates the chromatin of key genes involved in B cell signaling, adhesion, migration, and immune function. Immunity 27:49–63
    [Google Scholar]
  57. 57. 
    Itoh-Nakadai A, Hikota R, Muto A, Kometani K, Watanabe-Matsui M et al. 2014. The transcription repressors Bach2 and Bach1 promote B cell development by repressing the myeloid program. Nat. Immunol. 15:1171–80
    [Google Scholar]
  58. 58. 
    Swaminathan S, Huang C, Geng H, Chen Z, Harvey R et al. 2013. BACH2 mediates negative selection and p53-dependent tumor suppression at the pre–B cell receptor checkpoint. Nat. Med. 19:1014–22
    [Google Scholar]
  59. 59. 
    Muto A, Tashiro S, Nakajima O, Hoshino H, Takahashi S et al. 2004. The transcriptional programme of antibody class switching involves the repressor Bach2. Nature 429:566–71
    [Google Scholar]
  60. 60. 
    Zhang H, Chen Z, Miranda RN, Medeiros LJ, McCarty N 2017. Bifurcated BACH2 control coordinates mantle cell lymphoma survival and dispersal during hypoxia. Blood 130:763–76
    [Google Scholar]
  61. 61. 
    Cardenas MG, Yu W, Beguelin W, Teater MR, Geng H et al. 2016. Rationally designed BCL6 inhibitors target activated B cell diffuse large B cell lymphoma. J. Clin. Investig. 126:3351–62
    [Google Scholar]
  62. 62. 
    Ye BH, Lista F, Lo Coco F, Knowles DM, Offit K et al. 1993. Alterations of a zinc finger–encoding gene, BCL-6, in diffuse large-cell lymphoma. Science 262:747–50
    [Google Scholar]
  63. 63. 
    Duy C, Hurtz C, Shojaee S, Cerchietti L, Geng H et al. 2011. BCL6 enables Ph+ acute lymphoblastic leukaemia cells to survive BCR-ABL1 kinase inhibition. Nature 473:384–88
    [Google Scholar]
  64. 64. 
    Hurtz C, Chan LN, Geng H, Ballabio E, Xiao G et al. 2019. Rationale for targeting BCL6 in MLL-rearranged acute lymphoblastic leukemia. Genes Dev 33:1265–79
    [Google Scholar]
  65. 65. 
    Sommars MA, Ramachandran K, Senagolage MD, Futtner CR, Germain DM et al. 2019. Dynamic repression by BCL6 controls the genome-wide liver response to fasting and steatosis. eLife 8:e43922
    [Google Scholar]
  66. 66. 
    Senagolage MD, Sommars MA, Ramachandran K, Futtner CR, Omura Y et al. 2018. Loss of transcriptional repression by BCL6 confers insulin sensitivity in the setting of obesity. Cell Rep 25:3283–98.e6
    [Google Scholar]
  67. 67. 
    Oestreich KJ, Read KA, Gilbertson SE, Hough KP, McDonald PW et al. 2014. Bcl-6 directly represses the gene program of the glycolysis pathway. Nat. Immunol. 15:957–64
    [Google Scholar]
  68. 68. 
    Duy C, Yu JJ, Nahar R, Swaminathan S, Kweon SM et al. 2010. BCL6 is critical for the development of a diverse primary B cell repertoire. J. Exp. Med. 207:1209–21
    [Google Scholar]
  69. 69. 
    Reth M. 2002. Hydrogen peroxide as second messenger in lymphocyte activation. Nat. Immunol. 3:1129–34
    [Google Scholar]
  70. 70. 
    Jitschin R, Hofmann AD, Bruns H, Giessl A, Bricks J et al. 2014. Mitochondrial metabolism contributes to oxidative stress and reveals therapeutic targets in chronic lymphocytic leukemia. Blood 123:2663–72
    [Google Scholar]
  71. 71. 
    Sewastianik T, Szydlowski M, Jablonska E, Bialopiotrowicz E, Kiliszek P et al. 2016. FOXO1 is a TXN- and p300-dependent sensor and effector of oxidative stress in diffuse large B-cell lymphomas characterized by increased oxidative metabolism. Oncogene 35:5989–6000
    [Google Scholar]
  72. 72. 
    Shojaee S, Caeser R, Buchner M, Park E, Swaminathan S et al. 2015. Erk negative feedback control enables pre–B cell transformation and represents a therapeutic target in acute lymphoblastic leukemia. Cancer Cell 28:114–28
    [Google Scholar]
  73. 73. 
    Naughton R, Quiney C, Turner SD, Cotter TG 2009. Bcr-Abl-mediated redox regulation of the PI3K/AKT pathway. Leukemia 23:1432–40
    [Google Scholar]
  74. 74. 
    Mailloux RJ, McBride SL, Harper ME 2013. Unearthing the secrets of mitochondrial ROS and glutathione in bioenergetics. Trends Biochem. Sci. 38:592–602
    [Google Scholar]
  75. 75. 
    Xiao G, Chan LN, Klemm L, Braas D, Chen Z et al. 2018. B-cell-specific diversion of glucose carbon utilization reveals a unique vulnerability in B cell malignancies. Cell 173:470–84.e18
    [Google Scholar]
  76. 76. 
    Pallas DC, Shahrik LK, Martin BL, Jaspers S, Miller TB et al. 1990. Polyoma small and middle T antigens and SV40 small t antigen form stable complexes with protein phosphatase 2A. Cell 60:167–76
    [Google Scholar]
  77. 77. 
    Bensaad K, Tsuruta A, Selak MA, Vidal MN, Nakano K et al. 2006. TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell 126:107–20
    [Google Scholar]
  78. 78. 
    Ribas V, García-Ruíz C, Fernández-Checa JC 2014. Glutathione and mitochondria. Front. Pharmacol. 5:151
    [Google Scholar]
  79. 79. 
    Gout PW, Buckley AR, Simms CR, Bruchovsky N 2001. Sulfasalazine, a potent suppressor of lymphoma growth by inhibition of the Xc cystine transporter: a new action for an old drug. Leukemia 15:1633–40
    [Google Scholar]
  80. 80. 
    Cramer SL, Saha A, Liu J, Tadi S, Tiziani S et al. 2017. Systemic depletion of l-cyst(e)ine with cyst(e)inase increases reactive oxygen species and suppresses tumor growth. Nat. Med. 23:120–27
    [Google Scholar]
  81. 81. 
    Victora GD, Schwickert TA, Fooksman DR, Kamphorst AO, Meyer-Hermann M et al. 2010. Germinal center dynamics revealed by multiphoton microscopy with a photoactivatable fluorescent reporter. Cell 143:592–605
    [Google Scholar]
  82. 82. 
    Kojima H, Kobayashi A, Sakurai D, Kanno Y, Hase H et al. 2010. Differentiation stage–specific requirement in hypoxia-inducible factor 1α–regulated glycolytic pathway during murine B cell development in bone marrow. J. Immunol. 184:154–63
    [Google Scholar]
  83. 83. 
    Akkaya M, Traba J, Roesler AS, Miozzo P, Akkaya B et al. 2018. Second signals rescue B cells from activation-induced mitochondrial dysfunction and death. Nat. Immunol. 19:871–84
    [Google Scholar]
  84. 84. 
    Barrington SF, Mikhaeel NG, Kostakoglu L, Meignan M, Hutchings M et al. 2014. Role of imaging in the staging and response assessment of lymphoma: consensus of the International Conference on Malignant Lymphomas Imaging Working Group. J. Clin. Oncol. 32:3048–58
    [Google Scholar]
  85. 85. 
    Caro-Maldonado A, Wang R, Nichols AG, Kuraoka M, Milasta S et al. 2014. Metabolic reprogramming is required for antibody production that is suppressed in anergic but exaggerated in chronically BAFF-exposed B cells. J. Immunol. 192:3626–36
    [Google Scholar]
  86. 86. 
    Liu T, Kishton RJ, Macintyre AN, Gerriets VA, Xiang H et al. 2014. Glucose transporter 1–mediated glucose uptake is limiting for B-cell acute lymphoblastic leukemia anabolic metabolism and resistance to apoptosis. Cell Death Dis 5:e1470
    [Google Scholar]
  87. 87. 
    Jiang S, Yan W, Wang SE, Baltimore D 2018. Let-7 suppresses B cell activation through restricting the availability of necessary nutrients. Cell Metab 27:393–403.e4
    [Google Scholar]
  88. 88. 
    Doughty CA, Bleiman BF, Wagner DJ, Dufort FJ, Mataraza JM et al. 2006. Antigen receptor–mediated changes in glucose metabolism in B lymphocytes: role of phosphatidylinositol 3-kinase signaling in the glycolytic control of growth. Blood 107:4458–65
    [Google Scholar]
  89. 89. 
    Le A, Lane AN, Hamaker M, Bose S, Gouw A et al. 2012. Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells. Cell Metab 15:110–21
    [Google Scholar]
  90. 90. 
    McFadden K, Hafez AY, Kishton R, Messinger JE, Nikitin PA et al. 2016. Metabolic stress is a barrier to Epstein-Barr virus–mediated B-cell immortalization. PNAS 113:E782–90
    [Google Scholar]
  91. 91. 
    Caro P, Kishan AU, Norberg E, Stanley IA, Chapuy B et al. 2012. Metabolic signatures uncover distinct targets in molecular subsets of diffuse large B cell lymphoma. Cancer Cell 22:547–60
    [Google Scholar]
  92. 92. 
    Liu W, Le A, Hancock C, Lane AN, Dang CV et al. 2012. Reprogramming of proline and glutamine metabolism contributes to the proliferative and metabolic responses regulated by oncogenic transcription factor c-MYC. PNAS 109:8983–88
    [Google Scholar]
  93. 93. 
    Masle-Farquhar E, Broer A, Yabas M, Enders A, Broer S 2017. ASCT2 (SLC1A5)-deficient mice have normal B-cell development, proliferation, and antibody production. Front. Immunol. 8:549
    [Google Scholar]
  94. 94. 
    Yang L, Venneti S, Nagrath D 2017. Glutaminolysis: a hallmark of cancer metabolism. Annu. Rev. Biomed. Eng. 19:163–94
    [Google Scholar]
  95. 95. 
    Xiang Y, Stine ZE, Xia J, Lu Y, O'Connor RS et al. 2015. Targeted inhibition of tumor-specific glutaminase diminishes cell-autonomous tumorigenesis. J. Clin. Investig. 125:2293–306
    [Google Scholar]
  96. 96. 
    Haigis MC, Mostoslavsky R, Haigis KM, Fahie K, Christodoulou DC et al. 2006. SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells. Cell 126:941–54
    [Google Scholar]
  97. 97. 
    Jeong SM, Lee A, Lee J, Haigis MC 2014. SIRT4 protein suppresses tumor formation in genetic models of Myc-induced B cell lymphoma. J. Biol. Chem. 289:4135–44
    [Google Scholar]
  98. 98. 
    Wise DR, DeBerardinis RJ, Mancuso A, Sayed N, Zhang XY et al. 2008. Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. PNAS 105:18782–87
    [Google Scholar]
  99. 99. 
    Gao P, Tchernyshyov I, Chang TC, Lee YS, Kita K et al. 2009. c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature 458:762–65
    [Google Scholar]
  100. 100. 
    Shaffer AL3rd, Young RM, Staudt LM 2012. Pathogenesis of human B cell lymphomas. Annu. Rev. Immunol. 30:565–610
    [Google Scholar]
  101. 101. 
    Carracedo A, Cantley LC, Pandolfi PP 2013. Cancer metabolism: fatty acid oxidation in the limelight. Nat. Rev. Cancer 13:227–32
    [Google Scholar]
  102. 102. 
    Weisel FJ, Mullett SJ, Elsner RA, Menk AV, Trivedi N et al. 2020. Germinal center B cells selectively oxidize fatty acids for energy while conducting minimal glycolysis. Nat. Immunol. 21:331–42
    [Google Scholar]
  103. 103. 
    Liu PP, Liu J, Jiang WQ, Carew JS, Ogasawara MA et al. 2016. Elimination of chronic lymphocytic leukemia cells in stromal microenvironment by targeting CPT with an antiangina drug perhexiline. Oncogene 35:5663–73
    [Google Scholar]
  104. 104. 
    DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB 2008. The biology of cancer: Metabolic reprogramming fuels cell growth and proliferation. Cell Metab 7:11–20
    [Google Scholar]
  105. 105. 
    Lam WY, Jash A, Yao CH, D'Souza L, Wong R et al. 2018. Metabolic and transcriptional modules independently diversify plasma cell lifespan and function. Cell Rep 24:2479–92.e6
    [Google Scholar]
  106. 106. 
    Wang LW, Wang Z, Ersing I, Nobre L, Guo R et al. 2019. Epstein-Barr virus subverts mevalonate and fatty acid pathways to promote infected B-cell proliferation and survival. PLOS Pathog 15:e1008030
    [Google Scholar]
  107. 107. 
    Wang LW, Shen H, Nobre L, Ersing I, Paulo JA et al. 2019. Epstein-Barr virus–induced one-carbon metabolism drives B cell transformation. Cell Metab 30:539–55.e11
    [Google Scholar]
  108. 108. 
    Pourdehnad M, Truitt ML, Siddiqi IN, Ducker GS, Shokat KM, Ruggero D 2013. Myc and mTOR converge on a common node in protein synthesis control that confers synthetic lethality in Myc-driven cancers. PNAS 110:11988–93
    [Google Scholar]
  109. 109. 
    Nilsson LM, Forshell TZ, Rimpi S, Kreutzer C, Pretsch W et al. 2012. Mouse genetics suggests cell-context dependency for Myc-regulated metabolic enzymes during tumorigenesis. PLOS Genet 8:e1002573
    [Google Scholar]
  110. 110. 
    Maddocks ODK, Athineos D, Cheung EC, Lee P, Zhang T et al. 2017. Modulating the therapeutic response of tumours to dietary serine and glycine starvation. Nature 544:372–76
    [Google Scholar]
  111. 111. 
    Yang M, Vousden KH. 2016. Serine and one-carbon metabolism in cancer. Nat. Rev. Cancer 16:650–62
    [Google Scholar]
  112. 112. 
    Loeb E, Hill JM, Hill NO, MacLellan A, Khan A et al. 1970. Treatment of acute leukemia with l-asparaginase. Recent Results Cancer Res 33:204–18
    [Google Scholar]
  113. 113. 
    Whitecar JP Jr., Bodey GP, Hill CS Jr., Samaan NA. 1970. Effect of l-asparaginase on carbohydrate metabolism. Metabolism 19:581–86
    [Google Scholar]
  114. 114. 
    Dominguez-Sola D, Victora GD, Ying CY, Phan RT, Saito M et al. 2012. The proto-oncogene MYC is required for selection in the germinal center and cyclic reentry. Nat. Immunol. 13:1083–91
    [Google Scholar]
  115. 115. 
    Klein U, Dalla-Favera R. 2008. Germinal centres: role in B-cell physiology and malignancy. Nat. Rev. Immunol. 8:22–33
    [Google Scholar]
  116. 116. 
    Kim JW, Gao P, Liu YC, Semenza GL, Dang CV 2007. Hypoxia-inducible factor 1 and dysregulated c-Myc cooperatively induce vascular endothelial growth factor and metabolic switches hexokinase 2 and pyruvate dehydrogenase kinase 1. Mol. Cell. Biol. 27:7381–93
    [Google Scholar]
  117. 117. 
    Murphy TA, Dang CV, Young JD 2013. Isotopically nonstationary 13C flux analysis of Myc-induced metabolic reprogramming in B-cells. Metab. Eng. 15:206–17
    [Google Scholar]
  118. 118. 
    Li F, Wang Y, Zeller KI, Potter JJ, Wonsey DR et al. 2005. Myc stimulates nuclearly encoded mitochondrial genes and mitochondrial biogenesis. Mol. Cell. Biol. 25:6225–34
    [Google Scholar]
  119. 119. 
    Loven J, Orlando DA, Sigova AA, Lin CY, Rahl PB et al. 2012. Revisiting global gene expression analysis. Cell 151:476–82
    [Google Scholar]
  120. 120. 
    Xie H, Tang CH, Song JH, Mancuso A, Del Valle JR et al. 2018. IRE1α RNase-dependent lipid homeostasis promotes survival in Myc-transformed cancers. J. Clin. Investig. 128:1300–16
    [Google Scholar]
  121. 121. 
    Kronke J, Udeshi ND, Narla A, Grauman P, Hurst SN et al. 2014. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science 343:301–5
    [Google Scholar]
  122. 122. 
    Lu G, Middleton RE, Sun H, Naniong M, Ott CJ et al. 2014. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science 343:305–9
    [Google Scholar]
  123. 123. 
    Faubert B, Boily G, Izreig S, Griss T, Samborska B et al. 2013. AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo. Cell Metab 17:113–24
    [Google Scholar]
  124. 124. 
    Ramadani F, Bolland DJ, Garcon F, Emery JL, Vanhaesebroeck B et al. 2010. The PI3K isoforms p110α and p110δ are essential for pre–B cell receptor signaling and B cell development. Sci. Signal. 3:ra60
    [Google Scholar]
  125. 125. 
    Deau MC, Heurtier L, Frange P, Suarez F, Bole-Feysot C et al. 2014. A human immunodeficiency caused by mutations in the PIK3R1 gene. J. Clin. Investig. 124:3923–28
    [Google Scholar]
  126. 126. 
    Avery DT, Kane A, Nguyen T, Lau A, Nguyen A et al. 2018. Germline-activating mutations in PIK3CD compromise B cell development and function. J. Exp. Med. 215:2073–95
    [Google Scholar]
  127. 127. 
    Browne CD, Del Nagro CJ, Cato MH, Dengler HS, Rickert RC 2009. Suppression of phosphatidylinositol 3,4,5-trisphosphate production is a key determinant of B cell anergy. Immunity 31:749–60
    [Google Scholar]
  128. 128. 
    Miletic AV, Anzelon-Mills AN, Mills DM, Omori SA, Pedersen IM et al. 2010. Coordinate suppression of B cell lymphoma by PTEN and SHIP phosphatases. J. Exp. Med. 207:2407–20
    [Google Scholar]
  129. 129. 
    Stadanlick JE, Cancro MP. 2008. BAFF and the plasticity of peripheral B cell tolerance. Curr. Opin. Immunol. 20:158–61
    [Google Scholar]
  130. 130. 
    Mackay F, Woodcock SA, Lawton P, Ambrose C, Baetscher M et al. 1999. Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune manifestations. J. Exp. Med. 190:1697–710
    [Google Scholar]
  131. 131. 
    Davidson A. 2010. Targeting BAFF in autoimmunity. Curr. Opin. Immunol. 22:732–39
    [Google Scholar]
  132. 132. 
    Steri M, Orru V, Idda ML, Pitzalis M, Pala M et al. 2017. Overexpression of the cytokine BAFF and autoimmunity risk. N. Engl. J. Med. 376:1615–26
    [Google Scholar]
  133. 133. 
    Coope A, Torsoni AS, Velloso LA 2016. Mechanisms in endocrinology: metabolic and inflammatory pathways on the pathogenesis of type 2 diabetes. Eur. J. Endocrinol. 174:R175–87
    [Google Scholar]
  134. 134. 
    de Haas EC, Oosting SF, Lefrandt JD, Wolffenbuttel BH, Sleijfer DT, Gietema JA 2010. The metabolic syndrome in cancer survivors. Lancet Oncol 11:193–203
    [Google Scholar]
  135. 135. 
    Gelelete CB, Pereira SH, Azevedo AM, Thiago LS, Mundim M et al. 2011. Overweight as a prognostic factor in children with acute lymphoblastic leukemia. Obesity 19:1908–11
    [Google Scholar]
  136. 136. 
    Orgel E, Tucci J, Alhushki W, Malvar J, Sposto R et al. 2014. Obesity is associated with residual leukemia following induction therapy for childhood B-precursor acute lymphoblastic leukemia. Blood 124:3932–38
    [Google Scholar]
  137. 137. 
    Butturini AM, Dorey FJ, Lange BJ, Henry DW, Gaynon PS et al. 2007. Obesity and outcome in pediatric acute lymphoblastic leukemia. J. Clin. Oncol. 25:2063–69
    [Google Scholar]
  138. 138. 
    Weiser MA, Cabanillas ME, Konopleva M, Thomas DA, Pierce SA et al. 2004. Relation between the duration of remission and hyperglycemia during induction chemotherapy for acute lymphocytic leukemia with a hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone/methotrexate-cytarabine regimen. Cancer 100:1179–85
    [Google Scholar]
  139. 139. 
    Castillo JJ, Ingham RR, Reagan JL, Furman M, Dalia S, Mitri J 2014. Obesity is associated with increased relative risk of diffuse large B-cell lymphoma: a meta-analysis of observational studies. Clin. Lymphoma Myeloma Leuk. 14:122–30
    [Google Scholar]
  140. 140. 
    Castillo JJ, Mull N, Reagan JL, Nemr S, Mitri J 2012. Increased incidence of non-Hodgkin lymphoma, leukemia, and myeloma in patients with diabetes mellitus type 2: a meta-analysis of observational studies. Blood 119:4845–50
    [Google Scholar]
  141. 141. 
    Crowson CS, Matteson EL, Davis JM 3rd, Gabriel SE 2013. Contribution of obesity to the rise in incidence of rheumatoid arthritis. Arthritis Care Res 65:71–77
    [Google Scholar]
  142. 142. 
    Kazazian NH, Wang Y, Roussel-Queval A, Marcadet L, Chasson L et al. 2019. Lupus autoimmunity and metabolic parameters are exacerbated upon high fat diet–induced obesity due to TLR7 signaling. Front. Immunol. 10:2015
    [Google Scholar]
  143. 143. 
    Alexander NJ, Smythe NL, Jokinen MP 1987. The type of dietary fat affects the severity of autoimmune disease in NZB/NZW mice. Am. J. Pathol. 127:106–21
    [Google Scholar]
  144. 144. 
    Kelley VE, Izui S. 1983. Enriched lipid diet accelerates lupus nephritis in NZB × W mice. Synergistic action of immune complexes and lipid in glomerular injury. Am. J. Pathol. 111:288–97
    [Google Scholar]
  145. 145. 
    Myers MG Jr., Leibel RL, Seeley RJ, Schwartz MW. 2010. Obesity and leptin resistance: distinguishing cause from effect. Trends Endocrinol. Metab. 21:643–51
    [Google Scholar]
  146. 146. 
    Lu Z, Xie J, Wu G, Shen J, Collins R et al. 2017. Fasting selectively blocks development of acute lymphoblastic leukemia via leptin-receptor upregulation. Nat. Med. 23:79–90
    [Google Scholar]
  147. 147. 
    Willett EV, Skibola CF, Adamson P, Skibola DR, Morgan GJ et al. 2005. Non-Hodgkin's lymphoma, obesity and energy homeostasis polymorphisms. Br. J. Cancer 93:811–16
    [Google Scholar]
  148. 148. 
    Amarilyo G, Iikuni N, Liu A, Matarese G, La Cava A 2014. Leptin enhances availability of apoptotic cell–derived self-antigen in systemic lupus erythematosus. PLOS ONE 9:e112826
    [Google Scholar]
  149. 149. 
    Lam QLK, Wang S, Ko OKH, Kincade PW, Lu L 2010. Leptin signaling maintains B-cell homeostasis via induction of Bcl-2 and cyclin D1. PNAS 107:13812–17
    [Google Scholar]
  150. 150. 
    Lourenço EV, Liu A, Matarese G, La Cava A 2016. Leptin promotes systemic lupus erythematosus by increasing autoantibody production and inhibiting immune regulation. PNAS 113:10637–42
    [Google Scholar]
  151. 151. 
    Monti S, Savage KJ, Kutok JL, Feuerhake F, Kurtin P et al. 2005. Molecular profiling of diffuse large B-cell lymphoma identifies robust subtypes including one characterized by host inflammatory response. Blood 105:1851–61
    [Google Scholar]
  152. 152. 
    Chiche J, Reverso-Meinietti J, Mouchotte A, Rubio-Patiño C, Mhaidly R et al. 2019. GAPDH expression predicts the response to R-CHOP, the tumor metabolic status, and the response of DLBCL patients to metabolic inhibitors. Cell Metab 29:1243–57.e10
    [Google Scholar]
  153. 153. 
    Trevino LR, Yang W, French D, Hunger SP, Carroll WL et al. 2009. Germline genomic variants associated with childhood acute lymphoblastic leukemia. Nat. Genet. 41:1001–5
    [Google Scholar]
  154. 154. 
    Van Nieuwenhove E, Garcia-Perez JE, Helsen C, Rodriguez PD, van Schouwenburg PA et al. 2018. A kindred with mutant IKAROS and autoimmunity. J. Allergy Clin. Immunol. 142:699–702.e12
    [Google Scholar]
  155. 155. 
    Hoshino A, Okada S, Yoshida K, Nishida N, Okuno Y et al. 2017. Abnormal hematopoiesis and autoimmunity in human subjects with germline IKZF1 mutations. J. Allergy Clin. Immunol. 140:223–31
    [Google Scholar]
  156. 156. 
    Yang W, Tang H, Zhang Y, Tang X, Zhang J et al. 2013. Meta-analysis followed by replication identifies loci in or near CDKN1B, TET3, CD80, DRAM1, and ARID5B as associated with systemic lupus erythematosus in Asians. Am. J. Hum. Genet. 92:41–51
    [Google Scholar]
  157. 157. 
    Lahoud MH, Ristevski S, Venter DJ, Jermiin LS, Bertoncello I et al. 2001. Gene targeting of Desrt, a novel ARID class DNA-binding protein, causes growth retardation and abnormal development of reproductive organs. Genome Res 11:1327–34
    [Google Scholar]
  158. 158. 
    Cichocki F, Wu CY, Zhang B, Felices M, Tesi B et al. 2018. ARID5B regulates metabolic programming in human adaptive NK cells. J. Exp. Med. 215:2379–95
    [Google Scholar]
  159. 159. 
    Fiorillo E, Orru V, Stanford SM, Liu Y, Salek M et al. 2010. Autoimmune-associated PTPN22 R620W variation reduces phosphorylation of lymphoid phosphatase on an inhibitory tyrosine residue. J. Biol. Chem. 285:26506–18
    [Google Scholar]
  160. 160. 
    Vang T, Congia M, Macis MD, Musumeci L, Orru V et al. 2005. Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant. Nat. Genet. 37:1317–19
    [Google Scholar]
  161. 161. 
    Hebbring SJ, Slager SL, Epperla N, Mazza JJ, Ye Z et al. 2013. Genetic evidence of PTPN22 effects on chronic lymphocytic leukemia. Blood 121:237–38
    [Google Scholar]
  162. 162. 
    Ekström Smedby K, Vajdic CM, Falster M, Engels EA, Martínez-Maza O et al. 2008. Autoimmune disorders and risk of non-Hodgkin lymphoma subtypes: a pooled analysis within the InterLymph Consortium. Blood 111:4029–38
    [Google Scholar]
  163. 163. 
    Hodgson K, Ferrer G, Montserrat E, Moreno C 2011. Chronic lymphocytic leukemia and autoimmunity: a systematic review. Haematologica 96:752–61
    [Google Scholar]
  164. 164. 
    Jonsson V, Wiik A, Hou-Jensen K, Christiansen M, Ryder LP et al. 1999. Autoimmunity and extranodal lymphocytic infiltrates in lymphoproliferative disorders. J. Intern. Med. 245:277–86
    [Google Scholar]
  165. 165. 
    Singh M, Jackson KJL, Wang JJ, Schofield P, Field MA et al. 2020. Lymphoma driver mutations in the pathogenic evolution of an iconic human autoantibody. Cell 180:878–94.e19
    [Google Scholar]
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