Abstract
Platelet production requires compartmentalized caspase activation within megakaryocytes. This eventually results in platelet release in conjunction with apoptosis of the remaining megakaryocyte. Recent studies have indicated that in low-risk myelodysplastic syndromes (MDS) and idiopathic thrombocytopenic purpura (ITP), premature cell death of megakaryocytes may contribute to thrombocytopenia. Different cell death patterns have been identified in megakaryocytes in these disorders. Growing evidence suggests that, besides apoptosis, necrosis and autophagic cell death, may also be programmed. Therefore, programmed cell death (PCD) can be classified in apoptosis, a caspase-dependent process, apoptosis-like, autophagic and necrosis-like PCD, which are predominantly caspase-independent processes. In MDS, megakaryocytes show features of necrosis-like PCD, whereas ITP megakaryocytes demonstrate predominantly characteristics of apoptosis-like PCD (para-apoptosis). Triggers for these death pathways are largely unknown. In MDS, the interaction of Fas/Fas-ligand might be of importance, whereas in ITP antiplatelet autoantibodies recognizing common antigens on megakaryocytes and platelets might be involved. These findings illustrate that cellular death pathways in megakaryocytes are recruited in both physiological and pathological settings, and that different forms of cell death can occur in the same cell depending on the stimulus and the cellular context. Elucidation of the underlying mechanisms might lead to novel therapeutic interventions.
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References
Patel SR, Hartwig JH, Italiano Jr JE . The biogenesis of platelets from megakaryocyte proplatelets. J Clin Invest 2005; 115: 3348–3354.
Radley JM, Haller CJ . Fate of senescent megakaryocytes in the bone marrow. Br J Haematol 1983; 53: 277–287.
Zauli G, Vitale M, Falcieri E, Gibellini D, Bassini A, Celeghini C et al. In vitro senescence and apoptotic cell death of human megakaryocytes. Blood 1997; 90: 2234–2243.
De Botton S, Sabri S, Daugas E, Zermati Y, Guidotti JE, Hermine O et al. Platelet formation is the consequence of caspase activation within megakaryocytes. Blood 2002; 100: 1310–1317.
Edinger AL, Thompson CB . Death by design: apoptosis, necrosis and autophagy. Curr Opin Cell Biol 2004; 16: 663–669.
Kitanaka C, Kuchino Y . Caspase-independent programmed cell death with necrotic morphology. Cell Death Differ 1999; 6: 508–515.
Leist M, Jäättelä M . Four deaths and a funeral: from caspases to alternative mechanisms. Nat Rev Mol Cell Biol 2001; 2: 589–598.
Assunção Guimarães C, Linden R . Programmed cell deaths. Apoptosis and alternative deathstyles. Eur J Biochem 2004; 271: 1638–1650.
Otsuki Y, Li Z, Shibata MA . Apoptotic detection methods – from morphology to gene. Prog Histochem Cytochem 2003; 38: 275–339.
Kroemer G, El-Deiry WS, Golstein P, Peter ME, Vaux D, Vandenabeele P et al. Nomenclature committee on cell death. Classification of cell death: recommendations of the nomenclature committee on cell death. Cell Death Differ 2005; 12: 1463–1467.
Kroemer G, Jäättelä M . Lysosomes and autophagy in cell death control. Nat Rev Cancer 2005; 5: 886–897.
Levine B, Yuan J . Autophagy in cell death: an innocent convict? J Clin Invest 2005; 115: 2679–2688.
Green DR, Kroemer G . Pharmacological manipulation of cell death: clinical applications in sight? J Clin Invest 2005; 115: 2610–2617.
Parker JE, Mufti GJ . The myelodysplastic syndromes: a matter of life or death. Acta Haematol 2004; 111: 78–99.
Liesveld JL, Jordan CT, Phillips II GL . The hematopoietic stem cell in myelodysplasia. Stem Cells 2004; 22: 590–599.
Yoshida Y, Mufti GJ . Apoptosis and its significance in MDS: controversies revisited. Leuk Res 1999; 23: 777–785.
Mundle SD . Lingering biologic dilemmas about the status of the progenitor cells in myelodysplasia. Arch Med Res 2003; 34: 515–519.
Steensma DP, Bennett JM . The myelodysplastic syndromes: diagnosis and treatment. Mayo Clin Proc 2006; 81: 104–130.
Houwerzijl EJ, Blom NR, van der Want JJ, Louwes H, Esselink MT, Smit JW et al. Increased peripheral platelet destruction and caspase-3-independent programmed cell death of bone marrow megakaryocytes in myelodysplastic patients. Blood 2005; 105: 3472–3479.
Cines DB, Cassileth PA, Kiss JE . Danazol therapy in myelodysplasia. Ann Intern Med 1985; 103: 58–60.
Bourgeois E, Caulier MT, Rose C, Dupriez B, Bauters F, Fenaux P . Role of splenectomy in the treatment of myelodysplastic syndromes with peripheral thrombocytopenia: a report on six cases. Leukemia 2001; 15: 950–953.
Hofmann WK, Kalina U, Koschmieder S, Seipelt G, Hoelzer D, Ottmann OG . Defective megakaryocytic development in myelodysplastic syndromes. Leuk Lymphoma 2000; 38: 13–19.
van Lom K, Houtsmuller AB, van Putten WL, Slater RM, Löwenberg B . Cytogenetic clonality analysis of megakaryocytes in myelodysplastic syndrome by dual-color fluorescence in situ hybridization and confocal laser scanning microscopy. Genes Chromosomes Cancer 1999; 25: 332–338.
Adams JA, Liu Yin JA, Brereton ML, Briggs M, Burgess R, Hyde K . The in vitro effect of pegylated recombinant human megakaryocyte growth and development factor (PEG rHuMGDF) on megakaryopoiesis in normal subjects and patients with myelodysplasia and acute myeloid leukaemia. Br J Haematol 1997; 99: 139–146.
Kalina U, Hofmann WK, Koschmieder S, Wagner S, Kauschat D, Hoelzer D et al. Alteration of c-mpl-mediated signal transduction in CD34(+) cells from patients with myelodysplastic syndromes. Exp Hematol 2000; 28: 1158–1163.
Zwierzina H, Rollinger-Holzinger I, Nuessler V, Herold M, Meng YG . Endogenous serum thrombopoietin concentrations in patients with myelodysplastic syndromes. Leukemia 1998; 12: 59–64.
Hatfill SJ, Fester ED, Steytler JG . Apoptotic megakaryocyte dysplasia in the myelodysplastic syndromes. Hematol Pathol 1992; 6: 87–93.
Bogdanovic AD, Trpinac DP, Jankovic GM, Bumbasirevic VZ, Obradovic M, Colovic MD . Incidence and role of apoptosis in myelodysplastic syndrome: morphological and ultrastructural assessment. Leukemia 1997; 11: 656–659.
Shetty V, Hussaini S, Broady-Robinson L, Allampallam K, Mundle S, Borok R et al. Intramedullary apoptosis of hematopoietic cells in myelodysplastic syndrome patients can be massive: apoptotic cells recovered from high-density fraction of bone marrow aspirates. Blood 2000; 96: 1388–1392.
Shetty V, Hussaini S, Alvi S, Joshi L, Shaher A, Dangerfield B et al. Excessive apoptosis, increased phagocytosis, nuclear inclusion bodies and cylindrical confronting cisternae in bone marrow biopsies of myelodysplastic syndrome patients. Br J Haematol 2002; 116: 817–825.
Kurotaki H, Tsushima Y, Nagai K, Yagihashi S . Apoptosis, bcl-2 expression and p53 accumulation in myelodysplastic syndrome, myelodysplastic-syndrome-derived acute myelogenous leukemia and de novo acute myelogenous leukemia. Acta Haematol 2000; 102: 115–123.
Bouscary D, De Vos J, Guesnu M, Jondeau K, Viguier F, Melle J et al. Fas/Apo-1 (CD95) expression and apoptosis in patients with myelodysplastic syndromes. Leukemia 1997; 11: 839–845.
Brada SJ, van de Loosdrecht AA, Koudstaal J, de Wolf JT, Vellenga E . Limited numbers of apoptotic cells in fresh paraffin embedded bone marrow samples of patients with myelodysplastic syndrome. Leuk Res 2004; 28: 921–925.
Li X, Pu Q . Megakaryocytopoiesis and apoptosis in patients with myelodysplastic syndromes. Leuk Lymphoma 2005; 46: 387–391.
Kitagawa M, Yamaguchi S, Takahashi M, Tanizawa T, Hirokawa K, Kamiyama R . Localization of Fas and Fas ligand in bone marrow cells demonstrating myelodysplasia. Leukemia 1998; 12: 486–492.
Vanden Berghe T, van Loo G, Saelens X, Van Gurp M, Brouckaert G, Kalai M et al. Differential signaling to apoptotic and necrotic cell death by Fas-associated death domain protein FADD. J Biol Chem 2004; 279: 7925–7933.
Fuhler GM, Drayer AL, Vellenga E . Decreased phosphorylation of protein kinase B and extracellular signal-regulated kinase in neutrophils from patients with myelodysplasia. Blood 2003; 101: 1172–1180.
Harker LA . Thrombokinetics in idiopathic thrombocytopenic purpura. Br J Haematol 1970; 19: 95–104.
Diggs LW, Hewlett JB . A study of the bone marrow from thirty-six patients with idiopathic hemorrhagic (thrombopenic) purpura. Blood 1948; 3: 1090–1104.
Ballem PJ, Segal GM, Stratton JR, Gernsheimer T, Adamson JW, Slichter SJ . Mechanisms of thrombocytopenia in chronic autoimmune thrombocytopenic purpura. Evidence of both impaired platelet production and increased platelet clearance. J Clin Invest 1987; 80: 33–40.
Louwes H, Zeinali Lathori OA, Vellenga E, de Wolf JT . Platelet kinetic studies in patients with idiopathic thrombocytopenic purpura. Am J Med 1999; 106: 430–434.
Pisciotta AV, Stefanini M, Dameshek W . Studies on platelets. X. Morphologic characteristics of megakaryocytes by phase contrast microscopy in normals and in patients with idiopathic thrombocytopenic purpura. Blood 1953; 8: 703–723.
Houwerzijl EJ, Blom NR, van der Want JJ, Esselink MT, Koornstra JJ, Smit JW et al. Ultrastructural study shows morphologic features of apoptosis and para-apoptosis in megakaryocytes from patients with idiopathic thrombocytopenic purpura. Blood 2004; 103: 500–506.
Centurione L, Di Baldassarre A, Zingariello M, Bosco D, Gatta V, Rana RA et al. Increased and pathologic emperipolesis of neutrophils within megakaryocytes associated with marrow fibrosis in GATA-1(low) mice. Blood 2004; 104: 3573–3580.
Thiele J, Lorenzen J, Manich B, Kvasnicka HM, Zirbes TK, Fischer R . Apoptosis (programmed cell death) in idiopathic (primary) osteo-/myelofibrosis: naked nuclei in megakaryopoiesis reveal features of para-apoptosis. Acta Haematol 1997; 97: 137–143.
Craddock Jr CG, Adams WS, Perry S, Lawrence JS . The dynamics of platelet production as studied by a depletion technique in normal and irradiated dogs. J Lab Clin Med 1955; 45: 906–919.
Zucker-Franklin D, Termin CS, Cooper MC . Structural changes in the megakaryocytes of patients infected with the human immune deficiency virus (HIV-1). Am J Pathol 1989; 134: 1295–1303.
Ucar C, Oren H, Irken G, Ates H, Atabay B, Turker M et al. Investigation of megakaryocyte apoptosis in children with acute and chronic idiopathic thrombocytopenic purpura. Eur J Haematol 2003; 70: 347–352.
McMillan R, Wang L, Tomer A, Nichol J, Pistillo J . Suppression of in vitro megakaryocyte production by antiplatelet autoantibodies from adult patients with chronic ITP. Blood 2004; 103: 1364–1369.
Ohshima K, Karube K, Shimazaki K, Kamma H, Suzumiya J, Hamasaki M et al. Imbalance between apoptosis and telomerase activity in myelodysplastic syndromes: possible role in ineffective hemopoiesis. Leuk Lymphoma 2003; 44: 1339–1346.
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This work was supported by a grant from the JK de Cock Foundation and the Dutch Cancer Society (2003–2920).
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Houwerzijl, E., Blom, N., van der Want, J. et al. Megakaryocytic dysfunction in myelodysplastic syndromes and idiopathic thrombocytopenic purpura is in part due to different forms of cell death. Leukemia 20, 1937–1942 (2006). https://doi.org/10.1038/sj.leu.2404385
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DOI: https://doi.org/10.1038/sj.leu.2404385
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