Abstract
Since aplastic anemia—paroxysmal nocturnal hemoglobinuria syndrome was reported in 1967, the overlap of idiopathic aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria (PNH) has been well known.The link between the 2 diseases became even more evident when immunosuppressive therapy improved survival of patients with severe AA. More than 10% of patients with AA develop clinically evident PNH. Moreover, flow cytometric analysis demonstrates that the majority of patients with AA have a subclinical percentage of granulocytes with PNH phenotype. Some of them have clearly recognizable PNH clones. Granulocytes with a PNH phenotype are also often found in normal individuals, though at much smaller percentages of cells. This finding suggests that a PNH clone is expanded in AA, consistent with a hypothesis that blood cells from patients with PNH are more resistant to an autoimmune environment. Survival of PNH clones in pathologic bone marrow may account for limited expansion of PNH clones; however, additional genetic change(s) that confers cells with growth phenotype may be required for the full development of PNH.
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References
Lewis SM, Dacie JV. The aplastic anaemia-paroxysmal nocturnal haemoglobinuria syndrome.Br J Haematol. 1967;13:236–251.
Tichelli A, Gratwohl A, Wursch A, Nissen C, Speck B. Late haematological complications in severe aplastic anaemia.Br J Haematol. 1988;69:413–418.
de Planque MM, Bacigalupo A, Wursch A, et al. Long-term follow-up of severe aplastic anaemia patients treated with antithymocyte globulin. Severe Aplastic Anaemia Working Party of the European Cooperative Group for Bone Marrow Transplantation (EBMT).Br J Haematol. 1989;73:121–126.
Najean Y, Haguenauer O. Long-term (5 to 20 years) evolution of nongrafted aplastic anemias. The Cooperative Group for the Study of Aplastic and Refractory Anemias.Blood. 1990;76:2222–2228.
Young NS, Maciejewski J. The pathophysiology of acquired aplastic anemia.N Engl J Med. 1997;336:1365–1372.
Young NS. Hematopoietic cell destruction by immune mechanisms in acquired aplastic anemia.Semin Hematol. 2000;37:3–14.
Rosse WF. New insights into paroxysmal nocturnal hemoglobinuria.Curr Opin Hematol. 2001;8:61–67.
Luzzatto L, Bessler M, Rotoli B. Somatic mutations in paroxysmal nocturnal hemoglobinuria: a blessing in disguise?Cell. 1997;88:1–4.
Watanabe R, Murakami Y, Marmor MD, et al. Initial enzyme for glycosylphosphatidylinositol biosynthesis requires PIG-P and is regulated by DPM2.EMBO J. 2000;19:4402–4411.
Kostova Z, Rancour DM, Menon AK, Orlean P. Photoaffinity labelling with P3-(4-azidoanilido)uridine 5′-triphosphate identifies Gpi3p as the UDP-GlcNAc-binding subunit of the enzyme that catalyses formation of GlcNAc-phosphatidylinositol, the first glycolipid intermediate in glycosylphosphatidylinositol synthesis.Biochem J. 2000;350:815–822.
Takeda J, Miyata T, Kawagoe K, et al. Deficiency of the GPI anchor caused by a somatic mutation of thePIG-A gene in paroxysmal nocturnal hemoglobinuria.Cell. 1993;73:703–711.
Nishimura J, Hirota T, Kanakura Y, et al. Long-term support of hematopoiesis by a single cell clone in patients with paroxysmal nocturnal hemoglobinuria.Blood. In press.
Terstappen L, Nguyen M, Huang S, Lazarus HM, Medof ME. Defective and normal haematopoietic stem cells in paroxysmal nocturnal haemoglobinuria.Br J Haematol. 1993;84:504–514.
Yamada N, Miyata T, Maeda K, Kitani T, Takeda J, Kinoshita T. Somatic mutations of thePIG-A gene found in Japanese patients with paroxysmal nocturnal hemoglobinuria.Blood. 1995;85:885–892.
Araten DJ, Nafa K, Pakdeesuwan K, Luzzatto L. Clonal populations of hematopoietic cells with paroxysmal nocturnal hemoglobinuria genotype and phenotype are present in normal individuals.Proc Natl Acad Sci U S A. 1999;96:5209–5214.
Kawagoe K, Kitamura D, Okabe M, et al. GPI-anchor deficient mice: implications for clonal dominance of mutant cells in paroxysmal nocturnal hemoglobinuria.Blood. 1996;87:3600–3606.
Rosti V, Tremmi G, Soares V, Pandolfi PP, Luzzatto L, Bessler M. Murine embryonic stem cells withoutpig-a gene activity are competent for hematopoiesis with the PNH phenotype but not for clonal expansion.J Clin Invest. 1997;100:1028–1036.
Murakami Y, Kinoshita T, Maeda Y, Nakano T, Kosaka H, Takeda J. Different roles of glycosylphosphatidylinositol in various hematopoietic cells as revealed by model mice of paroxysmal nocturnal hemoglobinuria.Blood. 1999;94:2963–2970.
Tremml G, Dominguez C, Rosti V, et al. Increased sensitivity to complement and a decreased red cell life span in mice mosaic for a non-functionalPiga gene.Blood. 1999;94:2945–2954.
Keller P, Tremml G, Rosti V, Bessler M. X inactivation and somatic cell selection rescue female mice carrying a Piga-null mutation.Proc Natl Acad Sci U S A. 1999;96:7479–7483.
Keller P, Payne JL, Tremml G, et al. FES-Cre targets phosphatidylinositol glycan class A (PIGA) inactivation to hamatopoietic stem cells in the bone marrow.J Exp Med. 2001;194:581–589.
Schubert J, Vogt HG, Zielinska Skowronek M, et al. Development of the glycosylphosphatidylinositol-anchoring defect characteristic for paroxysmal nocturnal hemoglobinuria in patients with aplastic anemia.Blood. 1994;83:2323–2328.
Schrezenmeier H, Hertenstein B, Wagner B, Raghavachar A, Heimpel HA. Pathogenetic link between aplastic anemia and paroxysmal nocturnal hemoglobinuria is suggested by a high frequency of aplastic anemia patients with a deficiency of phosphatidylinositol glycan anchored proteins.Exp Hematol. 1995;23:81–87.
Griscelli-Bennaceur A, Gluckman E, Scrobohaci ML, et al. Aplastic anemia and paroxysmal nocturnal hemoglobinuria: search for a pathogenetic link.Blood. 1995;85:1354–1363.
De Lord C, Tooze JA, Saso R, Marsh JCW, Gordon-Smith EC. Deficiency of glycosylphosphatidyl inositol-anchored proteins in patients with aplastic anaemia does not affect response to immuno-suppressive therapy.Br J Haematol. 1998;101:90–93.
Azenishi Y, Ueda E, Machii T, et al. CD59-deficient blood cells and PIG-A gene abnormalities in Japanese patients with aplastic anaemia.Br J Haematol. 1999;104:523–529.
Dunn DE, Tanawattanacharoen P, Boccuni P, et al. Paroxysmal nocturnal hemoglobinuria cells in patients with bone marrow failure syndromes.Ann Intern Med. 1999;131:401–408.
Wang H, Chuhjo T, Yamazaki H, et al. Relative increase of granulocytes with a paroxysmal nocturnal haemoglobinuria phenotype in aplastic anaemia patients: the high prevalence at diagnosis.Eur J Haematol. 2001;66:200–205.
Mukhina GL, Buckley JT, Barber JP, Jones RJ, Brodsky RA. Multilineage glycosylphosphatidylinositol anchor-deficient haematopoiesis in untreated aplastic anaemia.Br J Haematol. 2001;115:476–482.
Nagarajan S, Brodsky RA, Young NS, Medof ME. Genetic defects underlying paroxysmal nocturnal hemoglobinuria that arises out of aplastic anemia.Blood. 1995;86:4656–4661.
Rotoli B, Luzzatto L. Paroxysmal nocturnal haemoglobinuria.Baillieres Clin Haematol. 1989;2:113–138.
Young NS. The problem of clonality in aplastic anemia: Dr Dameshek’s riddle, restated.Blood. 1992;79:1385–1392.
Young NS, Maciejewski JP. Genetic and environmental effects in paroxysmal nocturnal hemoglobinuria: this littlePIG-A goes “Why? Why? Why?”J Clin Invest. 2000;106:637–641.
Karadimitris A, Luzzatto L. The cellular pathogenesis of paroxysmal nocturnal haemoglobinuria.Leukemia. 2001;15:1148–1152.
Hollander N, Selvaraj P, Springer TA. Biosynthesis and function of LFA-3 in human mutant cells deficient in phosphatidylinositol-anchored proteins.J Immunol. 1988;141:4283–4290.
Karadimitris A, Notaro R, Koehne G, Roberts IA, Luzzatto L. PNH cells are as sensitive to T-cell-mediated lysis as their normal counterparts: implications for the pathogenesis of paroxysmal nocturnal haemoglobinuria.Br J Haematol. 2000;111:1158–1163.
Murakami Y, Kosaka H, Takeda J, Kinoshita T. Two possible mechanisms for escape of GPI- cells from the immunological attack. Paper presented at: International Symposium on PNH and Related Diseases; August 28–29,2001;Tokyo, Japan.
Groh V, Rhinehart R, Randolph-Habecker J, Topp MS, Riddell SR, Spies T. Costimulation of CD8αβ T cells by NKG2D via engagement by MIC induced on virus-infected cells.Nat Immunol. 2001;2:255–260.
Cosman D, Mullberg J, Sutherland CL, et al. ULBPs, novel MHC class I-related molecules, bind to CMV glycoprotein UL16 and stimulate NK cytotoxicity through the NKG2D receptor.Immunity. 2001;14:123–133.
Girardi M, Oppenheim DE, Steele CR, et al. Regulation of cutaneous malignancy by γδ T cells.Science. 2001;294:605–609.
Rammensee H-G, Friede T, Stevanovic S. MHC ligands and peptide motifs: first listing.Immunogenetics. 1995;41:178–228.
Joyce S, Woods AS, Yewdell JW, et al. Natural ligand of mouse CD1d1: cellular glycosylphosphatidylinositol.Science. 1998;279:1541–1544.
Kawano T, Cui J, Koezuka Y, et al. CD1d-restricted and TCR-medi-ated activation of Vα14 NKT cells by glycosylceramides.Science. 1997;278:1626–1629.
Cerwenka A, Bakker ABH, McClanahan T, et al. Retinoic acid early inducible genes define a ligand family for the activating NKG2D receptor in mice.Immunity. 2000;12:721–727.
Brodsky RA, Vala MS, Barber JP, Medof ME, Jones RJ. Resistance to apoptosis caused by PIG-A gene mutations in paroxysmal nocturnal hemoglobinuria.Proc Natl Acad Sci U S A. 1997;94:8756–8760.
Horikawa K, Nakakuma H, Kawaguchi T, et al. Apoptosis resistance of blood cells from patients with paroxysmal nocturnal hemoglobinuria, aplastic anemia, and myelodysplastic syndrome.Blood. 1997;90:2716–2722.
Ware RE, Nishimura J, Moody MA, Smith C, Rosse WF, Howard TA. The PIG-A mutation and absence of glycosylphosphatidyli-nositol-linked proteins do not confer resistance to apoptosis in paroxysmal nocturnal hemoglobinuria.Blood. 1998;92:2541–2550.
Bastisch I, Tiede A, Deckert M, Ziolek A, Schmidt RE, Schubert J. Glycosylphosphatidylinositol (GPI)-deficient Jurkat T cells as a model to study functions of GPI-anchored proteins.Clin Exp Immunol. 2000;122:49–54.
Chen R, Nagarajan S, Prince GM, et al. Impaired growth and elevated Fas receptor expression inPIGA+ stem cells in primary paroxysmal nocturnal hemoglobinuria.J Clin Invest. 2000;106:689–696.
Schrezenmeier H, HildebrandA, Rojewski M, Hacker H, Heimpel H, Raghavachar A. Paroxysmal nocturnal haemoglobinuria: a replacement of haematopoietic tissue?Acta Haematol. 2000;103:41–48.
Lyakisheva A, Felda O, Ganser A, Schmidt RE, Schubert J. Paroxysmal nocturnal hemoglobinuria: differential gene expression of EGR-1 and TAXREB107.Exp Hematol. 2002;30:18–25.
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Kinoshita, T., Inoue, N. Relationship Between Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria. Int J Hematol 75, 117–122 (2002). https://doi.org/10.1007/BF02982015
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DOI: https://doi.org/10.1007/BF02982015