Skip to main content
SpringerLink
Log in

The role of apoptosis in regulating hematopoiesis and hematopoietic stem cells

  • Published:
Immunologic Research Aims and scope Submit manuscript

Abstract

Apoptosis, or the ability of cells to die in an orderly and highly regulated manner, is essential for normal development and homeostasis of multicellular organisms. Diseases in which deregulation of this process is implicated include autoimmune diseases, cancer and Alzheimer's disease. The importance of apoptosis for the development and function of lymphoid cells has been extensively investigated. Less clear is the role apoptosis plays in regulating early progenitor and stem cell compartments. This question is being investigated using, a transgenic mouse model, H2K-BCL-2, in which all hematopoietic cells have an increased resistance to apoptosis. The same transgenic model is also being used to address the question whether protection against apoptosisc an increase system-wide resistance to lethal challenges such as irradiation and chemotherapeutic agents.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Kerr JF, Wyllie AH, Currie AR: Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 1972;26:239–257.

    PubMed  CAS  Google Scholar 

  2. Rathmell JC, Thompson CB: The central effectors of cell death in the immune system. Annu Rev Immunol 1999;17:781–828.

    Article  PubMed  CAS  Google Scholar 

  3. Steinman RM, Turley S, Mellman I, Inaba K: The induction of tolerance by dendritic cells that have capturedapoptotic cells. J Exp Med 2000;191:411–416.

    Article  PubMed  CAS  Google Scholar 

  4. Desnoyers S, Hengartner MO: Genetics of apoptosis. Adv Pharmacol 1997;41:35–56.

    Article  PubMed  CAS  Google Scholar 

  5. Vaux DL, Cory S, Adams JM: Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature 1988;335:440–442.

    Article  PubMed  CAS  Google Scholar 

  6. Vaux DL, Wiessman IL, Kim SK: Prevention of programmed cell death in Caenorhabditis elegans by human bcl-2. Science 1992;258:1955–1957.

    Article  PubMed  CAS  Google Scholar 

  7. Strasser A, Huang DC, Vaux DL: The role of the bcl-2/ced-9 gene family in cancer and general implications of defects in cell death control for tumourigenesis and resistance to chemotherapy. Biochim Biophys Acta 1997;1333:F151–178.

    Google Scholar 

  8. Raff M: Cell suicide for beginners. Nature 1998;396:119–122

    Article  PubMed  CAS  Google Scholar 

  9. Chao DT, Korsmeyer SJ: BCL-2 family: regulators of cell death. Annu Rev Immunol 1998;16:395–419.

    Article  PubMed  CAS  Google Scholar 

  10. Green DR, Reed JC: Mitochondria and apoptosis. Science 1998;281:1309–1312.

    Article  PubMed  CAS  Google Scholar 

  11. Thornberry NA, Lazebnik Y: Caspases: enemies within. Science 1998;281:1312–1316.

    Article  PubMed  CAS  Google Scholar 

  12. Adams JM, Cory S: The Bcl-2 prolein family: arbiters of cell survival Science 1998;281:1322–1326.

    Article  PubMed  CAS  Google Scholar 

  13. Ashkenazi A, Dixit VM: Apoptosis control by death and decoy receptors. Curr Opin Cell Biol 1999;11:255–260.

    Article  PubMed  CAS  Google Scholar 

  14. Li H, Yuan J: Deciphering the pathways of life and death. Curr Opin Cell Biol 1999;11:261–266.

    Article  PubMed  CAS  Google Scholar 

  15. Budihardjo I, Oliver H, Lutter M, Luo X, Wang X: Biochemical pathways of caspase activation during apoptosis. Annu Rev Cell Dev Biol 1999;15:269–290.

    Article  PubMed  CAS  Google Scholar 

  16. Los M, Wesselborg S, Schulze-Osthoff K: The role of caspases in development, immunity, and apoptotic signal transduction: lessons from knockout mice. Immunity 1999;10:629–639.

    Article  PubMed  CAS  Google Scholar 

  17. Cross TG, Scheel-Toellner D, Henriquez NV, Deacon E, Salmon M, Lord JM: Serine/threonine protein kinases and apoptosis. Exp Cell Res 2000;256:34–41.

    Article  PubMed  CAS  Google Scholar 

  18. Antonsson B, Martinon JC: The Bcl-2 protein family. Exp Cell Res 2000;256:50–57.

    Article  PubMed  CAS  Google Scholar 

  19. Walczak H, Krammer PH: The CD95 (APO-1/Fas) and the TRAIL (APO-2L) apoptosis systems. Exp Cell Res 2000;256:58–66.

    Article  PubMed  CAS  Google Scholar 

  20. Zheng TS, Flavell RA: Divinations and surprises: genetic analysis of caspase function in mice. Exp Cell Res 2000;256:67–73.

    Article  PubMed  CAS  Google Scholar 

  21. Barcena A, Park SW, Banapour B, Muench MO, Mechetner E: Expression of Fas/CD95 and Bcl-2 by primitive hematopoietic progenitors freshly isolated from human fetal liver. Blood 1996;88:2013–2025.

    PubMed  CAS  Google Scholar 

  22. Josefsen D, Myklebust JH, Lynch DH, Stokke T, Blomhoff HK, Smeland EB: Fas ligand promotes cell survival of immature human bone marrow CD34+CD38-hematopoietic progenitor cells by suppressing apoplosis. Exp Hematol 1999;27:1451–1459.

    Article  PubMed  CAS  Google Scholar 

  23. Ashkenazi A, Dixit VM: Death receptors: signaling and modulation. Science 1998;281:1305–1308.

    Article  PubMed  CAS  Google Scholar 

  24. Haraguchi M, Torii S, Matsuzawa S, et al: Apoptotic protease activating factor 1 (Apaf-1)-independent cell death suppression by Bcl-2 J Exp Med 2000;191:1709–1720.

    Article  PubMed  CAS  Google Scholar 

  25. Takeda K, Kaisho T, Yoshida N, Takeda J, Kishimoto T, Akira S: Stat3 activation is responsible for IL-6-dependent T cell proliferation through preventing apoptosis: generation and characterization of T cell-specific Stat3-deficient mice. J Immunol 1998;161:4652–4660.

    PubMed  CAS  Google Scholar 

  26. Shirogane T, Fukada T, Muller JM, Shima DT, Hibi M, Hirano T: Synergistic roles for P im-1 and c-Myc in STAT3-mediated cell cycle progression and antiapoptosis. Immunity 1999;11:709–719.

    Article  PubMed  CAS  Google Scholar 

  27. Tsujimoto Y, Cossman J, Jaffe E, Croce CM: Involvement of the bcl-2 gene in human follicular lymphoma. Science 1985;228:1440–1443.

    Article  PubMed  CAS  Google Scholar 

  28. Bakhshi A, Jensen JP, Goldman P, et al: Cloning the chromosomal breakpointoft(14;18) human lymphomas: clustering around JH on chromosome 14 and near a transcriptional unit on 18. Cell 1985;41:899–906.

    Article  PubMed  CAS  Google Scholar 

  29. Cleary ML, Smith SD, Sklar J: Cloning and structural analysis of cDNAs for bcl-2 and a hybrid bcl-2/immunoglobulin transcript resulting from the t(14;18) translocation. Cell 1986;47:19–28.

    Article  PubMed  CAS  Google Scholar 

  30. Acton D, Jacobs H, Domen J, Berns A: Bcl-2 reduces lymphomagenesis in deltaV-TCR beta transgenic mice. Oncogene 1997;14:2497–2501.

    Article  PubMed  CAS  Google Scholar 

  31. Schendel SL, Montal M, Reed JC: Bcl-2 family proteins as ion-channels. Cell Death Differ 1998;5:372–380.

    Article  PubMed  CAS  Google Scholar 

  32. Oltvai ZN, Korsmeyer SJ: Check-points of due ling dimers foil death wishes. Cell 1994;79:189–192.

    Article  PubMed  CAS  Google Scholar 

  33. Zha J, Harada H, Yang E, Jockel J, Korsmeyer SJ: Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-X(L). Cell 1996;87:619–628.

    Article  PubMed  CAS  Google Scholar 

  34. del Peso L, Gonzalez-Garcia M, Page C, Herrera R, Nunez G: Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt. Science 1997;278:687–689.

    Article  PubMed  Google Scholar 

  35. Datta SR, Dudek H, Tao X, et al: Aktphosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 1997;91:231–241.

    Article  PubMed  CAS  Google Scholar 

  36. Ruvolo PP, Deng X, Carr BK, May WS: A functional role for mitochondrial protein kinase Calpha in Bcl2 phosphorylation and suppression of apoptosis. J Biol Chem 1998;273:25,436–25,442.

    Article  CAS  Google Scholar 

  37. McCubrey JA, May WS, Duronio V, Mufson A. Serine/threonine phosphorylation in cytokine signal transduction. Leukemia 2000;14:9–21.

    Article  PubMed  CAS  Google Scholar 

  38. Domen J, vander Lugt NM, Acton D, Laird PW, Linders K, Berns A: Pim-1 levels determine the size of early B lymphoid compartments in bone marrow. J Exp Med 1993;178:1665–1673.

    Article  PubMed  CAS  Google Scholar 

  39. Domen J, van der Lugt NM, Laird PW, et al: Impaired interleukin-3 response in Pim-1-deficient bone marrow-derived mast cells. Blood 1993;82:1445–1452.

    PubMed  CAS  Google Scholar 

  40. Yang J, Liu X, Bhalla K, et al: Prevention of apoptosis by Bcl-2: release of cytochromec from mitochondria blocked. Science 1997;275:1129–1132.

    Article  PubMed  CAS  Google Scholar 

  41. Kluck RM, Bossy-Wetzel E, Green DR, Newmeyer DD: The release of cytochrome c from mitochondria: a primary site for Bcl-2 regulation of apoptosis. Science 1997;275:1132–1136.

    Article  PubMed  CAS  Google Scholar 

  42. Veis DJ, Sorenson CM, Shutter JR, Korsmeyer SJ: Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair. Cell 1993;75:229–240.

    Article  PubMed  CAS  Google Scholar 

  43. Motoyama N, Wang F, Roth KA, et al: Massive cell death of immature hematopoietic cells and neurons in Bcl-x-deficient mice. Science 1995;267:1506–1510.

    Article  PubMed  CAS  Google Scholar 

  44. Print CG, Loveland KL, Gibson L, et al: Apoptosis regulator bcl-w is essential for spermatogenesis but appears otherwise redundant Proc. Natl Acad Sci USA 1998;95:12,424–12,431.

    Article  CAS  Google Scholar 

  45. Ross AJ, Waymire KG, Moss JE, et al: Testicular degeneration in Bclw-deficient mice. Nat Genet 1998;18:251–256.

    Article  PubMed  CAS  Google Scholar 

  46. Rinkenberger JL, Horning S, Klocke B, Roth K, Korsmeyer SJ: Mcl-1 deficiency results in peri-implantation embryonic lethality. Genes Dev 2000;14:23–27.

    PubMed  CAS  Google Scholar 

  47. Deckwerth TL, Elliott JL, Knudson CM, Johnson EM, Jr., Snider WD, Korsmeyer SJ: BAX is required for neuronal death after trophic factor deprivation and during development. Neuron 1996;17:401–411.

    Article  PubMed  CAS  Google Scholar 

  48. Yin XM, Wang K, Gross A, et al: Bid-deficient mice are resistant to Fas-induced hepatocellular apoptosis. Nature 1999;400:886–891.

    Article  PubMed  CAS  Google Scholar 

  49. Bouillet P, Metcalf D, Huang DC, et al: Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity. Science 1999;286:1735–1738.

    Article  PubMed  CAS  Google Scholar 

  50. King KL, Cidlowski JA: Cell cycle regulation and apoptosis. Annu Rev Physiol 1998;60:601–617.

    Article  PubMed  CAS  Google Scholar 

  51. O'Connor L, Huang DC, O'Reilly LA, Strasser A: A poptosisand cell division. Curr Opin Cell Biol 2000;12:257–263.

    Article  PubMed  Google Scholar 

  52. Mazel S, Hurtrum D, Petrie HT: Regulation of cell division cycle progression by bcl-2 expression: a potential mechanism for inhibition of programmed cell death. J Exp Med 1996;183:2219–2226.

    Article  PubMed  CAS  Google Scholar 

  53. O'Reilly LA, Huang DC, Strasser A: The cell death inhibitor Bcl-2 and its homologues influence comtrol of cell cycle entry. Embo J 1996;15:6979–6990.

    PubMed  Google Scholar 

  54. Vairo G, Innes KM, Adams JM: Bcl-2 has a cell cycle inhibitory function separable from its enhancement of cell survival. Oncogene 1996;13:1511–1519.

    PubMed  CAS  Google Scholar 

  55. Linette GP, Li Y, Roth K, Korsmeyer SJ: Cross talk between cell death and cell cycle progression: BCL-2 regulates NFAT-mediated activation. Proc Natl Acad Sci USA 1996;93:9545–9552.

    Article  PubMed  CAS  Google Scholar 

  56. Domen J, Cheshier SH, Weissman IL: The role of apoptosis in the regulation of hematopoietic stem cells: Overex pression of Bcl-2 increases both their number and repopulation potential. J Exp Med 2000;191:253–264.

    Article  PubMed  CAS  Google Scholar 

  57. Brady HJ, Gil-Gomez G, Kirberg J, Berns AJ. Bax alpha perturbs T cell development and affects cell cycle entry of T cells. Embo J 1996;15:6991–7001.

    PubMed  CAS  Google Scholar 

  58. Gil-Gomez G, Berns A, Brady HJ: A link between cell cycle and cell death: Bax and Bcl-2 modulate Cdk2 activation during thymocyte apoptosis. Embo J 1998;17:7209–7218.

    Article  PubMed  CAS  Google Scholar 

  59. Huang DC, O'Reilly LA, Strasser A, Cory S: The anti-apoptosis function of Bcl-2 can be genetically separated from its inhibitory effect on cell cycle entry. Embo J 1997;16:4628–4638.

    Article  PubMed  CAS  Google Scholar 

  60. Naismith JH, Sprang SR: Modularity in the TNF-receptor family. Trends Biochem Sci 1998;23:74–79.

    Article  PubMed  CAS  Google Scholar 

  61. Trauth BC, Klas C, Peters AM, et al: Monoclonal antibody-mediated tumor regression by induction of apoptosis. Science 1989;245:301–305.

    Article  PubMed  CAS  Google Scholar 

  62. Yonehara S, Ishii A, Yonehara M: A cell-killing monoclonal antibody (anti-Fas) to a cell surface antigenco-dow nregulated with the receptor of tumor necrosis factor. J Exp Med 1989;169:1747–1756.

    Article  PubMed  CAS  Google Scholar 

  63. Chan FK, Chun HJ, Zheng L, Siegel RM, Bui KL, Lenardo MJ: A domain in TNF receptors that mediates ligand-independent receptor assembly and signaling. Science 2000;288:2351–2354

    Article  PubMed  CAS  Google Scholar 

  64. Siegel RM, Frederiksen JK, Zacharias DA, et al: Fas preassociation required for apoptosis signaling and dominant inhibition by pathogenic mutations. Science 2000;288:2354–2357.

    Article  PubMed  CAS  Google Scholar 

  65. Cryns V, Yuan J: Proteases to die for. Genes Dev 1998;12:1551–1570.

    PubMed  CAS  Google Scholar 

  66. Nagata S: Fas ligand-induced apoptosis. Annu Rev Genet 1999;33:29–55.

    Article  PubMed  CAS  Google Scholar 

  67. Matsumoto M, Fu YX, Molina H, Chaplin DD: Lymphotoxin-alpha-deficient and TNF receptor I-deficient mice define developmental and functional characteristics of germinal centers. Immunol Rev 1997;156:137–144.

    Article  PubMed  CAS  Google Scholar 

  68. Vaux DL: Caspases and apoptosis—biology and terminology. Cell Death Differ 1999;6:493–494.

    Article  PubMed  CAS  Google Scholar 

  69. Borner C, Monney L: Apoptosis without caspases: an inefficient molecular guillotine. Cell Death Differ 1999;6:497–507.

    Article  PubMed  CAS  Google Scholar 

  70. Du C, Fang M, Li L, Wang X: Smac a Mitochondrial Protein that Promotes Cytochrome c-Dependent Caspase Activation by Eliminating IAP Inhibition. Cell 2000;102:33–42.

    Article  PubMed  CAS  Google Scholar 

  71. Verhagen AM, Ekert PG, Pakusch M, et al: Identification of DIABLO, a Mammalian Protein that Promotes Apoptosis by Binding to and Antagonizing IAP Proteins. Cell 2000;102:43–54.

    Article  PubMed  CAS  Google Scholar 

  72. Colussi PA, Kumar S: Targeted, disruption of caspase genes in mice: what they tellus about the functions of individual caspases in apoptosis. Immunol Cell Biol 1999;77:58–63.

    Article  PubMed  CAS  Google Scholar 

  73. Pawliuk R, Eaves C, Humphries RK: Evidence of bothontogeny and transplant dose-regulated expansion of hematopoietic stem cells in vivo. Blood 1996;88:2852–2858.

    PubMed  CAS  Google Scholar 

  74. Iscove NN, Nawa K: Hematopoietic stem cell sex pandduring serial transplantation in vivo without apparent exhaustion. Curr Biol 1997;7:805–808.

    Article  PubMed  CAS  Google Scholar 

  75. Morrison SJ, Wandycz AM, Hemmati HD, Wright DE, Weissman IL: Identification of a lineage of multipotent hematopoietic progenitors. Development 1997;124:1929–1939.

    PubMed  CAS  Google Scholar 

  76. Gandy KL, Weissman IL: Tolerance of allogeneic heart grafts in mice simultaneously reconstituted with purified allogeneic hematopoietic stem cells. Transplantation 1998;65:295–304.

    Article  PubMed  CAS  Google Scholar 

  77. Weissman IL: Translatingstem and progenitor cell biology to the clinic: barriers and opportunities. Science 2000;287:1442–1446.

    Article  PubMed  CAS  Google Scholar 

  78. Shank B: Radio therapeutic principles of hematopoietic cell transplantation: in Thomas ED, Blume KG, Forman SJ, (ed.): Hematopoietic cell transplantation. Blackwell Science, Inc., 1999. p 151–167.

  79. Kaufmann SH, Earnshaw WC: Induction of apoplosis by cancer chemotherapy. Exp Cell Res 2000;256:42–49.

    Article  PubMed  CAS  Google Scholar 

  80. Domen J, Weissman IL: Self-renewal, differentiation or death: regulation and manipulation of hematopoietic stem cell fate. Mol Med Today 1999;5:201–208.

    Article  PubMed  CAS  Google Scholar 

  81. Traver D, Akashi K, Weissman IL, Lagasse E: Mice defective in two apoptosis pathways in the myeloid lineage develop acutemyeloblastic leukemia. Immunity 1998;9:47–57

    Article  PubMed  CAS  Google Scholar 

  82. Domen J, Gandy KL, Weissman IL. Systemic overexpression of BCL-2 in the hematopoietic system protects transgenic mice from the consequences of lethal irradiation. Blood 1998;91:2272–2282.

    PubMed  CAS  Google Scholar 

  83. Ogilvy S, Metcalf D, Print CG, Bath ML, Harris AW, Adams JM: Constitutive Bcl-2 expression throughout the hematopoietic compartment affects multiple lineages and enhances progenitorcell survival. Proc. Natl Acad Sci USA 1999;96:14,943–14,948.

    Article  CAS  Google Scholar 

  84. Strasser A, Harris AW, Cory S: bcl-2 transgene inhibits T cell death and perturbs thymic self-censorship. Cell 1991;67:889–899.

    Article  PubMed  CAS  Google Scholar 

  85. Setman, CL, Shutter JR, Hockenbery D, Kanagawa O, Korsmeyer SJ: bcl-2 inhibits multiple forms of apoptosis but not negative selection in thymocytes. Cell 1991;67:879–888.

    Article  Google Scholar 

  86. Katsumata M, Siegel RM, Louie DC, et al: Differential effects of Bcl-2 on T and B cells in transgenic mice. Proc Natl Acad Sci USA 1992;89:11,376–11,380.

    Article  CAS  Google Scholar 

  87. Strasser A, Harris AW, Huang DC, Krammer PH, Cory S: Bcl-2 and Fas/APO-1 regulate distinct pathways to lymphocyte apoptosis. Embo J 1995;14:6136–6147.

    PubMed  CAS  Google Scholar 

  88. Aguila HL, Weissman IL: Hematopoietic stem cells are not direct cytotoxic targets of natural killer cells. Blood 1996;87:1225–1231.

    PubMed  CAS  Google Scholar 

  89. Kondo M, Weissman IL, Akashi K: Identification of clonogenic common lymphoid progenitors in mouse bone marrow. Cell 1997;91:661–672.

    Article  PubMed  CAS  Google Scholar 

  90. Akashi K, Traver D, Miyamoto T, Weissman IL: A clonogenic common myeloid progenitor that gives rise to all myeloid lineages. Nature 2000;404:193–197.

    Article  PubMed  CAS  Google Scholar 

  91. Gandy KL, Domen J, Aguila H, Weissman IL: CD8+TCR+ and CD8+TCR-cells in whole bone marrow facilitate the engraftment of hematopoietic stem cells across allogeneic barriers. Immunity 1999;11:579–590.

    Article  PubMed  CAS  Google Scholar 

  92. Domen J, Weissman, IL: Hematopoietic stem cells need two signals to prevent apoptosis; BCL-2 can provide one of these, kitl/c-kit signalling the other. J Exp Med 2000;192:1707–1718.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Author notes

  1. Jos Domen

    Present address: Department of Medicine, Division of Medical Oncology and Transplantation, Duke University Medical Center, 247A Carl Building, Box 3225, 27710, Durham, NC

Authors and Affiliations

    Authors
    1. Jos Domen
      View author publications

      You can also search for this author in PubMed Google Scholar

    Rights and permissions

    Reprints and permissions

    About this article

    Cite this article

    Domen, J. The role of apoptosis in regulating hematopoiesis and hematopoietic stem cells. Immunol Res 22, 83–94 (2000). https://doi.org/10.1385/IR:22:2-3:83

    Download citation

    • Issue Date:

    • DOI: https://doi.org/10.1385/IR:22:2-3:83

    Key Words

    Search

    Navigation