Abstract
The importance of apoptosis, in combination with proliferation, in maintaining stable populations has become increasingly clear in the last decade. Perturbation of either of these processes can have serious consequences, and result in a variety of disorders. Moreover, as the players and pathways gradually emerge, it turns out that there are strong connections in the regulation of cell cycle progression and apoptosis. Apoptosis, proliferation, and the disorders resulting from aberrant regulation have been studied in a variety of cell types and systems. Hematopoietic stem cells (HSC) are defined as primitive mesenchymal cells that are capable of both self-renewal and differentiation into the various cell lineages that constitute the functioning hematopoietic system. Many (but certainly not all) mature hematopoietic cells are relatively short-lived, sometimes with a half-life in the order of days. Homeostasis requires the production of 108 (mouse) to 1011 (human) cells each day. All of these cells are ultimately derived from HSC that mostly reside in the bone marrow in adult mammals. The study of the regulation of HSC numbers has focussed mainly on the choice between self-renewal and differentiation, symmetric and asymmetric cell divisions. Recently, however, it has been directly demonstrated that apoptosis plays an important role in the regulation of hematopoietic stem cells in vivo.
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References
Till J, McCulloch E. A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiat Res 1961; 14: 213-224.
Visser JW, Bauman JG, Mulder AH, Eliason JF, de Leeuw AM. Isolation of murine pluripotent hemopoietic stem cells. J Exp Med 1984;159: 1576-1590.
Dexter TM, Spooncer E. Growth and differentiation in the hemopoietic system. Annu Rev Cell Biol 1987;3: 423-441.
Spangrude GJ, Heimfeld S, Weissman IL. Purification and characterization of mouse hematopoietic stem cells. Science 1988;241: 58-62.
Yoder MC, Hiatt K, Dutt P, Mukherjee P, Bodine DM, Orlic D. Characterization of definitive lymphohematopoietic stem cells in the day 9 murine yolk sac. Immunity 1997;7: 335-344.
Domen J, Weissman IL. Self-renewal, differentiation or death: Regulation and manipulation of hematopoietic stem cell fate. Mol Med Today 1999;5: 201-208.
Tavian M, Hallais MF, Peault B. Emergence of intraembryonic hematopoietic precursors in the pre-liver human embryo. Development 1999;126: 793-803.
Akashi K, Kondo M, Cheshier S, et al. Lymphoid development from stem cells and the common lymphocyte progenitors. Cold Spring Harbor Symp Quant Biol 1999;64: 1-12.
Weissman IL. Stem cells: Units of development, units of regeneration, and units in evolution. Cell 2000;100: 157-168.
Cumano A, Dieterlen-Lievre F, Godin I. The splanchnopleura/ AGM region is the prime site for the generation of multipotent hemopoietic precursors, in the mouse embryo. Vaccine 2000;18: 1621-1623.
de Bruijn MF, Speck NA, Peeters MC, Dzierzak E. Definitive hematopoietic stem cells first develop within the major arterial regions of the mouse embryo. EMBO J 2000;19: 2465-2474.
Lemischka IR. Clonal, in vivo behavior of the totipotent hematopoietic stem cell. Semin Immunol 1991;3: 349-355.
Cheshier SH, Morrison SJ, Liao X, Weissman IL. In vivo proliferation and cell cycle kinetics of long-term self-renewing hematopoietic stem cells. Proc Natl Acad Sci USA 1999;96: 3120-3125.
Wagemaker G. In vitro and in vivo expansion of stem cell populations. Vox Sang 1998;74: 463-466.
von Kalle C, Glimm H, Schulz G, Mertelsmann R, Henschler R. New developments in hematopoietic stem cell expansion. Curr Opin Hematol 1998;5: 79-86.
Audet J, Zandstra PW, Eaves CJ, Piret JM. Advances in hematopoietic stem cell culture. Curr Opin Biotechnol 1998;9: 146-151.
Aglietta M, Bertolini F, Carlo-Stella C, et al. Ex vivo expansion of hematopoietic cells and their clinical use. Haematologica 1998;83: 824-848.
Srour EF, Abonour R, Cornetta K, Traycoff CM. Ex vivo expansion of hematopoietic stem and progenitor cells: Are we there yet? J Hematother 1999;8: 93-102.
Bradford GB, Williams B, Rossi R, Bertoncello I. Quiescence, cycling, and turnover in the primitive hematopoietic stem cell compartment. Exp Hematol 1997;25: 445-453.
Domen J, Cheshier SH, Weissman IL. The role of apoptosis in the regulation of hematopoietic stem cellsOverexpression of Bcl-2 increases both their number and repopulation potential. J Exp Med 2000;191: 253-264.
Prockop DJ. Marrow stromal cells as stem cells for non-hematopoietic tissues. Science 1997;276: 71-74.
Fuchs E, Segre JA. Stem cells: A new lease on life. Cell 2000;100: 143-155.
Weissman IL. Translating stem and progenitor cell biology to the clinic: Barriers and opportunities. Science 2000;287: 1442-1446.
Gage FH. Mammalian neural stem cells. Science 2000;287: 1433-1438.
Ferrari G, Cusella-De Angelis G, Coletta M, et al. Muscle regeneration by bone marrow-derived myogenic progenitors. Science 1998;279: 1528-1530.
Eglitis MA, Mezey E. Hematopoietic cells differentiate into both microglia and macroglia in the brains of adult mice. Proc Natl Acad Sci USA 1997;94: 4080-4085.
Azizi SA, Stokes D, Augelli BJ, DiGirolamo C, Prockop DJ. Engraftment and migration of human bone marrow stromal cells implanted in the brains of albino rats-similarities to astrocyte grafts. Proc Natl Acad Sci USA 1998;95: 3908-3913.
Petersen BE, Bowen WC, Patrene KD, et al. Bone marrow as a potential source of hepatic oval cells. Science 1999;284: 1168-1170.
Bjornson CR, Rietze RL, Reynolds BA, Magli MC, Vescovi AL. Turning brain into blood: A hematopoietic fate adopted by adult neural stem cells in vivo. Science 1999;283: 534-537.
Jackson KA, Mi T, Goodell MA. Hematopoietic potential of stem cells isolated from murine skeletal muscle. Proc Natl Acad Sci USA 1999;96: 14482-14486.
Clarke DL, Johansson CB, Wilbertz J, et al. Generalized potential of adult neural stem cells. Science 2000;288: 1660-1663.
Lagasse E, Connors H, Al-Dhalimy M, et al. Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Nat Med 2000;6: 1229-1234.
Spangrude GJ, Johnson GR. Resting and activated subsets of mouse multipotent hematopoietic stem cells. Proc Natl Acad Sci USA 1990;87: 7433-7437.
Goodell MA, Brose K, Paradis G, Conner AS, Mulligan RC. Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. J Exp Med 1996;183: 1797-1803.
Storms RW, Trujillo AP, Springer JB, et al. Isolation of primitive human hematopoietic progenitors on the basis of aldehyde dehydrogenase activity. Proc Natl Acad Sci USA 1999;96: 9118-9123.
Uchida N, Weissman IL. Searching for hematopoietic stem cells: Evidence that Thy-1.1lo Lin-Sca-1+ cells are the only stem cells in C57BL/Ka-Thy-1.1 bone marrow. J Exp Med 1992;175: 175-184.
Ikuta K, Weissman IL. Evidence that hematopoietic stem cells express mouse c-kit but do not depend on steel factor for their generation. Proc Natl Acad Sci USA 1992;89: 1502-1506.
Wiesmann A, Phillips RL, Mojica M, et al. Expression of CD27 on murine hematopoietic stem and progenitor cells. Immunity 2000;12: 193-199.
Osawa M, Hanada K, Hamada H, Nakauchi H. Long-term lymphohematopoietic reconstitution by a single CD34-low/negative hematopoietic stem cell. Science 1996;273: 242-245.
Randall TD, Lund FE, Howard MC, Weissman IL. Expression of murine CD38 defines a population of long-term reconstituting hematopoietic stem cells. Blood 1996;87: 4057-4067.
Moore T, Huang S, Terstappen LW, Bennett M, Kumar V. Expression of CD43 on murine and human pluripotent hematopoietic stem cells. J Immunol 1994;153: 4978-4987.
Petrenko O, Beavis A, Klaine M, Kittappa R, Godin I, Lemischka IR. The molecular characterization of the fetal stem cell marker AA4. Immunity 1999;10: 691-700.
Bauman JG, de Vries P, Pronk B, Visser JW. Purification of murine hemopoietic stem cells and committed progenitors by fluorescence activated cell sorting using wheat germ agglutinin and monoclonal antibodies. Acta Histochem Suppl 1988;36: 241-253.
Morrison SJ, Weissman IL. The long-term repopulating subset of hematopoietic stem cells is deterministic and isolatable by phenotype. Immunity 1994;1: 661-673.
Kim M, Cooper DD, Hayes SF, Spangrude GJ. Rhodamine-123 staining in hematopoietic stem cells of young mice indicates mitochondrial activation rather than dye efflux. Blood 1998;91: 4106-4117.
Spangrude GJ, Brooks DM. Phenotypic analysis of mouse hematopoietic stem cells shows a Thy-1-negative subset. Blood 1992;80: 1957-1964.
Spangrude GJ, Brooks DM. Mouse strain variability in the expression of the hematopoietic stem cell antigen Ly-6A/E by bone marrow cells. Blood 1993;82: 3327-3332.
Morrison SJ, Hemmati HD, Wandycz AM, Weissman IL. The purification and characterization of fetal liver hematopoietic stem cells. Proc Natl Acad Sci USA 1995;92: 10302-10306.
Randall TD, Weissman IL. Phenotypic and functional changes induced at the clonal level in hematopoietic stem cells after 5-fluorouracil treatment. Blood 1997;89: 3596-3606.
Sato T, Laver JH, Ogawa M. Reversible Expression of CD34 by Murine Hematopoietic Stem Cells. Blood 1999;94: 2548-2554.
Spangrude GJ, Brooks DM, Tumas DB. Long-term repopulation of irradiated mice with limiting numbers of purified hematopoietic stem cells: in vivo expansion of stem cell phenotype but not function. Blood 1995;85: 1006-1016.
Zijlmans JM, Visser JW, Kleiverda K, Kluin PM, Willemze R, Fibbe WE. Modification of rhodamine staining allows identification of hematopoietic stem cells with preferential short-term or long-term bone marrow-repopulating ability. Proc Natl Acad Sci USA 1995;92: 8901-8905.
Morrison SJ, Wandycz AM, Hemmati HD, Wright DE, Weissman IL. Identification of a lineage of multipotent hematopoietic progenitors. Development 1997;124: 1929-1939.
Kondo M, Weissman IL, Akashi K. Identification of clonogenic common lymphoid progenitors in mouse bone marrow. Cell 1997;91: 661-672.
Galy A, Travis M, Cen D, Chen B. Human T, B, natural killer, and dendritic cells arise from a common bone marrow progenitor cell subset. Immunity 1995;3: 459-473.
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.
Muller-Sieburg CE, Riblet R. Genetic control of the frequency of hematopoietic stem cells in mice: Mapping of a candidate locus to chromosome 1. J Exp Med 1996;183: 1141-1150.
de Haan G, Van Zant G. Intrinsic and extrinsic control of hemopoietic stem cell numbers: Mapping of a stem cell gene. J Exp Med 1997;186: 529-536.
Gordon MY, Blackett NM. Reconstruction of the hematopoietic system after stem cell transplantation. Cell Transplant 1998;7: 339-344.
Lemischka IR, Raulet DH, Mulligan RC. Developmental potential and dynamic behavior of hematopoietic stem cells. Cell 1986;45: 917-927.
Necas E, Sefc L, Sulc K, Barthel E, Seidel HJ. Estimation of extent of cell death in different stages of normal murine hematopoiesis. Stem Cells 1998;16: 107-111.
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.
Richman CM, Weiner RS, Yankee RA. Increase in circulating stem cells following chemotherapy in man. Blood 1976;47: 1031-1039.
Appelbaum FR, Deeg HJ, Storb R, Graham TC, Charrier K, Bensinger W. Cure of malignant lymphoma in dogs with peripheral blood stem cell transplantation.Transplantation 1986;42: 19-22.
Abrams RA, McCormack K, Bowles C, Deisseroth AB. Cyclophosphamide treatment expands the circulating hematopoietic stem cell pool in dogs. J Clin Invest 1981;67: 1392-1399.
Siena S, Bregni M, Brando B, Ravagnani F, Bonadonna G, Gianni AM. Circulation of CD34+ hematopoietic stem cells in the peripheral blood of high-dose cyclophosphamide-treated patients: Enhancement by intravenous recombinant human granulocyte-macrophage colony-stimulating factor. Blood 1989;74: 1905-1914.
Molineux G, Pojda Z, Hampson IN, Lord BI, Dexter TM. Transplantation potential of peripheral blood stem cells induced by granulocyte colony-stimulating factor. Blood 1990;76: 2153-2158.
Zander AR, Lyding J, Bielack S. Transplantation with blood stem cells. Blood Cells 1991;17: 301-309.
Demirer T, Buckner CD, Bensinger WI. Optimization of peripheral blood stem cell mobilization. Stem Cells 1996;14: 106-116.
Repka T, Weisdorf D. Peripheral blood versus bone marrow for hematopoietic cell transplantation. Curr Opin Oncol 1998;10: 112-117.
Laterveer L, Lindley IJ, Hamilton MS, Willemze R, Fibbe WE. Interleukin-8 induces rapid mobilization of hematopoietic stem cells with radioprotective capacity and long-term myelolymphoid repopulating ability. Blood 1995;85: 2269-2275.
Morrison SJ, Wright DE, Weissman IL. Cyclophosphamide/ granulocyte colony-stimulating factor induces hematopoietic stem cells to proliferate prior to mobilization. Proc Natl Acad Sci USA 1997;94: 1908-1913.
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 progenitor cell survival. Proc Natl Acad SciUSA 1999;96: 14943-14948.
Fairbairn LJ, Cowling GJ, Reipert BM, Dexter TM. Suppression of apoptosis allows differentiation and development of a multipotent hemopoietic cell line in the absence of added growth factors. Cell 1993;74: 823-832.
Aguila HL, Weissman IL. Hematopoietic stem cells are not direct cytotoxic targets of natural killer cells. Blood 1996;87: 1225-1231.
Martin PJ, Hansen JA, Buckner CD, et al. Effects of in vitro depletion of T cells in HLA-identical allogeneic marrow grafts. Blood 1985;66: 664-672.
Gandy KL, Weissman IL. Tolerance of allogeneic heart grafts in mice simultaneously reconstituted with purified allogeneic hematopoietic stem cells. Transplantation 1998;65: 295-304.
Neipp M, Zorina T, Domenick MA, Exner BG, Ildstad ST. Effect of FLT3 ligand and granulocyte colony-stimulating factor on expansion and mobilization of facilitating cells and hematopoietic stem cells in mice: Kinetics and repopulating potential. Blood 1998;92: 3177-3188.
Martin PJ. Winning the battle of graft versus host. Nat Med 2000;6: 18-19.
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.
Shizuru JA, Jerabek L, Edwards CT, Weissman IL. Transplantation of purified hematopoietic stem cells: Requirements for overcoming the barriers of allogeneic engraftment. Biol Blood Marrow Transplant 1996;2: 3-14.
Wang B, El-Badri NS, Cherry, Good RA. Purified hematopoietic stem cells without facilitating cells can repopulate fully allogeneic recipients across entire major histocompatibility complex transplantation barrier in mice. Proc Natl Acad Sci USA 1997;94: 14632-14636.
Domen J, Weissman IL. Hematopoietic stem cells need two signals to prevent apoptosis;BCL-2 can provide one of these, Kitl/c-Kit signaling the other. J Exp Med 2000, 192;1707-1718.
Down JD, Boudewijn A, van Os R, Thames HD, Ploemacher RE. Variations in radiation sensitivity and repair among different hematopoietic stem cell subsets following fractionated irradiation. Blood 1995;86: 122-127.
McCarthy KF. Population size and radiosensitivity of murine hematopoietic endogenous long-term repopulating cells. Blood 1997;89: 834-841.
Strober S, Weissman IL. Immunosuppressive and tolerogenic effects of whole-body, total lymphoid, and regional irradiation. In: Salaman JR, ed. The current status of modern therapy. Vol. 7. Lancaster, England: MTP Press, 1981: 19-53.
Shank B. Radiotherapeutic principles of bone marrow transplantation. In: Forman SJ, Blume KG, Thomas ED, eds. Bone marrow transplantation. Boston: Blackwell Scientific Publications, 1994: 96-113.
Reed JC. Bcl-2 family proteins: regulators of apoptosis and chemoresistance in hematologic malignancies. Semin Hematol 1997;34: 9-19.
Hannun YA. Apoptosis and the dilemma of cancer chemotherapy. Blood 1997;89: 1845-1853.
Mesner PW, Jr., Budihardjo, II, Kaufmann SH. Chemotherapy-induced apoptosis. Adv Pharmacol1997;41:461-499.
Szilvassy SJ, Cory S. Phenotypic and functional characterization of competitive long-term repopulating hematopoietic stem cells enriched from 5-fluorouracil-treated murine marrow. Blood 1993;81: 2310-2320.
Hortobagyi GN, Buzdar AU, Theriault RL, et al. Randomized trial of high-dose chemotherapy and blood cell autografts for high-risk primary breast carcinoma. J Natl Cancer Inst 2000;92: 225-233.
Bashey A, Corringham S, Garrett J, et al. A phase II study of two cycles of high-dose chemotherapy with autologous stem cell support in patients with metastatic breast cancer who meet eligibility criteria for a single cycle. Bone Marrow Transplant 2000;25: 519-524.
Stadtmauer EA, O'Neill A, Goldstein LJ, et al. Conventional-dose chemotherapy compared with high-dose chemotherapy plus autologous hematopoietic stem-cell transplantation for metastatic breast cancer. Philadelphia Bone Marrow Transplant Group. N Engl J Med 2000;342: 1069-1076.
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.
Raff M. Cell suicide for beginners. Nature 1998;396: 119-122.
Chao DT, Korsmeyer SJ. BCL-2 family: Regulators of cell death. Annu Rev Immunol 1998;16: 395-419.
Green DR, Reed JC. Mitochondria and apoptosis. Science 1998;281: 1309-1312.
Thornberry NA, Lazebnik Y. Caspases: Enemies within. Science 1998;281: 1312-1316.
Adams JM, Cory S. The Bcl-2 protein family: arbiters of cell survival. Science 1998;281: 1322-1326.
Susin SA, Zamzami N, Kroemer G. Mitochondria as regulators of apoptosis: Doubt no more. Biochim Biophys Acta 1998;1366: 151-165.
Rathmell JC, Thompson CB. The central effectors of cell death in the immune system. Annu Rev Immunol 1999;17: 781-828.
Ashkenazi A, Dixit VM. Apoptosis control by death and decoy receptors. Curr Opin Cell Biol 1999;11: 255-260.
Lorenzo HK, Susin SA, Penninger J, Kroemer G. Apoptosis inducing factor (AIF): A phylogenetically old, caspase-independent effector of cell death. Cell Death Differ 1999;6: 516-524.
Li H, Yuan J. Deciphering the pathways of life and death. Curr Opin Cell Biol 1999;11: 261-266.
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.
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.
Skulachev VP. Mitochondrial physiology and pathology; concepts of programmed death of organelles, cells and organisms. Mol Aspects Med 1999;20: 139-184.
Miller LK. An exegesis of IAPs: Salvation and surprises from BIR motifs. Trends Cell Biol 1999;9: 323-328.
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.
Antonsson B, Martinou JC. The Bcl-2 protein family. Exp Cell Res 2000;256: 50-57.
Walczak H, Krammer PH. The CD95 (APO-1/Fas) and the TRAIL (APO-2L) apoptosis systems. Exp Cell Res 2000;256: 58-66.
Zheng TS, Flavell RA. Divinations and surprises: Genetic analysis of caspase function in mice. Exp Cell Res 2000;256: 67-73.
Green DR. Apoptotic pathways: Paper wraps stone blunts scissors. Cell 2000;102: 1-4.
Cai J, Yang J, Jones DP. Mitochondrial control of apoptosis: The role of cytochrome c. Biochim Biophys Acta 1998;1366: 139-149.
Susin SA, Lorenzo HK, Zamzami N, et al. Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 1999;397: 441-446.
Hausmann G, O'Reilly LA, van Driel R, et al. Pro-apoptotic apoptosis protease-activating factor 1 (Apaf-1) has a cytoplasmic localization distinct from Bcl-2 or Bcl-x(L). J Cell Biol 2000;149: 623-634.
Cryns V, Yuan J. Proteases to die for. Genes Dev 1998;12: 1551-1570.
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.
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.
Scaffidi C, Fulda S, Srinivasan A, et al. Two CD95 (APO-1/Fas) signaling pathways. EMBO J 1998;17: 1675-1687.
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.
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.
Ashkenazi A, Dixit VM. Death receptors: Signaling and modulation. Science 1998;281: 1305-1308.
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.
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 apoptosis. Exp Hematol 1999;27: 1451-1459.
Sherr CJ, Roberts JM. CDK inhibitors: Positive and negative regulators of G1-phase progression. Genes Dev 1999;13: 1501-1512.
Cheng T, Rodrigues N, Shen H, et al. Hematopoietic stem cell quiescence maintained by p21cip1/waf1. Science 2000;287: 1804-1808.
King KL, Cidlowski JA. Cell cycle regulation and apoptosis. Annu Rev Physiol 1998;60: 601-617.
Kasten MM, Giordano A. pRb and the cdks in apoptosis and the cell cycle. Cell Death Differ 1998;5: 132-140.
Guo M, Hay BA. Cell proliferation and apoptosis. Curr Opin Cell Biol 1999;11: 745-752.
O'Connor L, Huang DC, O'Reilly LA, Strasser A. Apoptosis and cell division. Curr Opin Cell Biol 2000;12: 257-263.
Evan G, Littlewood T. A matter of life and cell death. Science 1998;281: 1317-1322.
Oda K, Arakawa H, Tanaka T, et al. p53AIP1, a potential mediator of p53-dependent apoptosis, and its regulation by ser-46-phosphorylated p53. Cell 2000;102: 849-862.
Mazel S, Burtrum 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.
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.
O'Reilly LA, Huang DC, Strasser A. The cell death inhibitor Bcl-2 and its homologues influence control of cell cycle entry. Embo J 1996;15: 6979-6990.
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.
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.
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.
Li F, Ambrosini G, Chu EY, et al. Control of apoptosis and mitotic spindle checkpoint by survivin. Nature 1998;396: 580-584.
Uren AG, Beilharz T, O'Connell MJ, et al. Role for yeast inhibitor of apoptosis (IAP)-like proteins in cell division. Proc Natl Acad Sci USA 1999;96: 10170-10175.
Li F, Flanary PL, Altieri DC, Dohlman HG. Cell division regulation by BIR1, a member of the inhibitor of apoptosis family in yeast. J Biol Chem 2000;275: 6707-6711.
Reed JC, Bischoff JR. BIRinging chromosomes through cell division-and survivin’ the experience. Cell 2000;102: 545-548.
Park JR, Bernstein ID, Hockenbery DM. Primitive human hematopoietic precursors express Bcl-x but not Bcl-2. Blood 1995;86: 868-876.
Peters R, Leyvraz S, Perey L. Apoptotic regulation in primitive hematopoietic precursors. Blood 1998;92: 2041-2052.
Barcena A, Muench MO, Song KS, Ohkubo T, Harrison MR. Role of CD95/Fas and its ligand in the regulation of the growth of human CD34(++)CD38(?) fetal liver cells. Exp Hematol 1999;27: 1428-1439.
Sanz C, Benito A, Inohara N, Ekhterae D, Nunez G, Fernandez-Luna JL. Specific and rapid induction of the proapoptotic protein Hrk after growth factor withdrawal in hematopoietic progenitor cells. Blood 2000;95: 2742-2747.
Pierelli L, Marone M, Bonanno G, et al. Modulation of bcl-2 and p27 in human primitive proliferating hematopoietic progenitors by autocrine TGF-beta1 is a cell cycle-independent effect and influences their hematopoietic potential. Blood 2000;95: 3001-3009.
Phillips RL, Ernst RE, Brunk B, et al. The genetic program of hematopoietic stem cells. Science 2000;288: 1635-1640.
Prasad KV, Ao Z, Yoon Y, et al. CD27, a member of the tumor necrosis factor receptor family, induces apoptosis and binds to Siva, a proapoptotic protein. Proc Natl Acad Sci USA 1997;94: 6346-6351.
Niho Y, Asano Y. Fas/Fas ligand and hematopoietic progenitor cells. Curr Opin Hematol 1998;5: 163-165.
Maciejewski J, Selleri C, Anderson S, Young NS. Fas antigen expression on CD34+human marrow cells is induced by interferon gamma and tumor necrosis factor alpha and potentiates cytokine-mediated hematopoietic suppression in vitro. Blood 1995;85: 3183-3190.
Takenaka K, Nagafuji K, Harada M, et al. In vitro expansion of hematopoietic progenitor cells induces functional expression of Fas antigen (CD95). Blood 1996;88: 2871-2877.
Maciejewski JP, Selleri C, Sato T, Anderson S, Young NS. Increased expression of Fas antigen on bone marrow CD34+ cells of patients with aplastic anaemia. Br J Haematol 1995;91: 245-252.
Colussi PA, Kumar S. Targeted disruption of caspase genes in mice: What they tell us about the functions of individual caspases in apoptosis. Immunol Cell Biol 1999;77: 58-63.
Nagata S. Fas ligand-induced apoptosis. Annu Rev Genet 1999;33: 29-55.
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.
Yeh WC, Pompa JL, McCurrach ME, et al. FADD: Essential for embryo development and signaling from some, but not all, inducers of apoptosis. Science 1998;279: 1954-1958.
Yeh WC, Itie A, Elia AJ, et al. Requirement for Casper (c-FLIP) in regulation of death receptor-induced apoptosis and embryonic development. Immunity 2000;12: 633-642.
Cecconi F, Alvarez-Bolado G, Meyer BI, Roth KA, Gruss P. Apaf1 (CED-4 homolog) regulates programmed cell death in mammalian development. Cell 1998;94: 727-737.
Yoshida H, Kong YY, Yoshida R, et al. Apaf1 is required for mitochondrial pathways of apoptosis and brain development. Cell 1998;94: 739-750.
Donehower LA, Harvey M, Slagle BL, et al. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 1992;356: 215-221.
Lee EY, Chang CY, Hu N, et al. Mice deficient for Rb are nonviable and show defects in neurogenesis and haematopoiesis. Nature 1992;359: 288-294.
Jacks T, Fazeli A, Schmitt EM, Bronson RT, Goodell MA, Weinberg RA. Effects of an Rb mutation in the mouse. Nature 1992;359: 295-300.
Clarke AR, Maandag ER, van Roon M, et al. Requirement for a functional Rb-1 gene in murine development. Nature 1992;359: 328-330.
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.
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.
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: 12424-12431.
Ross AJ, Waymire KG, Moss JE, et al. Testicular degeneration in Bclw-deficient mice. Nat Genet 1998;18: 251-256.
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.
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.
Yin XM, Wang K, Gross A, et al. Bid-deficient mice are resistant to Fas-induced hepatocellular apoptosis. Nature 1999;400: 886-891.
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.
Kuida K, Zheng TS, Na S, et al. Decreased apoptosis in the brain and premature lethality in CPP32-deficient mice. Nature 1996;384: 368-372.
Varfolomeev EE, Schuchmann M, Luria V, et al. Targeted disruption of the mouse Caspase 8 gene ablates cell death induction by the TNF receptors, Fas/Apo1, and DR3 and is lethal prenatally. Immunity 1998;9: 267-276.
Kuida K, Haydar TF, Kuan CY, et al. Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking caspase9. Cell 1998;94: 325-337.
Hakem R, Hakem A, Duncan GS, et al. Differential requirement for caspase 9 in apoptotic pathways in vivo. Cell 1998;94: 339-352.
Li P, Allen H, Banerjee S, et al. Mice deficient in IL-1 beta-converting enzyme are defective in production of mature IL-1 beta and resistant to endotoxic shock. Cell 1995;80: 401-411.
Kuida K, Lippke JA, Ku G, et al. Altered cytokine export and apoptosis in mice deficient in interleukin-1 beta converting enzyme. Science 1995;267: 2000-2003.
Bergeron L, Perez GI, Macdonald G, et al. Defects in regulation of apoptosis in caspase-2-deficient mice. Genes Dev 1998;12: 1304-1314.
Wang S, Miura M, Jung YK, Zhu H, Li E, Yuan J. Murine caspase-11, an ICE-interacting protease, is essential for the activation of ICE. Cell 1998;92: 501-509.
Nakagawa T, Zhu H, Morishima N, et al. Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature 2000;403: 98-103.
Shinkai Y, Rathbun G, Lam KP, et al. RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Cell 1992;68: 855-867.
Nakayama K, Negishi I, Kuida K, et al. Disappearance of the lymphoid system in Bcl-2 homozygous mutant chimeric mice. Science 1993;261: 1584-1588.
Matsuzaki Y, Nakayama K, Tomita T, Isoda M, Loh DY, Nakauchi H. Role of bcl-2 in the development of lymphoid cells from the hematopoietic stem cell. Blood 1997;89: 853-862.
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Domen, J. The role of apoptosis in regulating hematopoietic stem cell numbers. Apoptosis 6, 239–252 (2001). https://doi.org/10.1023/A:1011347623402
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DOI: https://doi.org/10.1023/A:1011347623402