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Vol. 103, No. 1, 2000
Issue release date: March 2000

Paroxysmal Nocturnal Haemoglobinuria: A Replacement of Haematopoietic Tissue?

Schrezenmeier H. · Hildebrand A. · Rojewski M. · Häcker H. · Heimpel H. · Raghavachar A.
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Abstract

Acquired somatic mutations of the PIG-A gene lead to deficient expression of glycosyl-phosphatidyl-inositol-anchored proteins (GPI-AP) by haematopoietic cells and play a causative role in the pathogenesis of paroxysmal nocturnal haemoglobinuria (PNH). However, PIG-A mutations do not explain how the defective PNH clone can expand. It was hypothesized that a selection process conferring a relative advantage to the GPI-AP-deficient population is required. Since GPI-AP-deficient cells are also detectable in a substantial proportion of patients with otherwise typical aplastic anaemia (AA), the mechanisms inducing bone marrow failure might selectively spare the GPI-deficient cells. In order to examine the growth characteristics of GPI-AP-deficient cells in more detail, we performed repeated analyses of GPI-AP expression on peripheral blood cells in 41 patients with AA. We observed four patterns of the course of GPI-AP-deficient populations: (1) 13 patients showed normal expression of GPI-AP in the first analysis and in at least two follow-up studies at a median time of 709 days after the first analysis. (2) Secondary evolution of a GPI-AP-deficient population was a rare event. Only 4 patients with initially normal GPI-AP expression developed a GPI-AP-deficient population during follow up after immunosuppressive treatment. (3) Persistence of GPI-AP-deficient cells was observed in 16 patients during a median follow-up time of 774 days. However, in some patients, the size of the GPI-AP-deficient population increased substantially. (4) Disappearance of a GPI-AP-deficient population was observed in 8 patients. The time course of GPI-AP expression in relation to the treatment suggests that therapeutic interventions might modulate the ratio of normal versus GPI-AP-deficient haematopoiesis. Overall, these data argue against an ‘absolute growth advantage’ of GPI-AP-deficient cells. Our data are consistent with the hypothesis that haematopoietic failure caused by damage to normal haematopoiesis allows the outgrowth of a GPI-AP-deficient population. Thus, in at least some patients GPI-AP-deficient cells might pre-exist at a very low percentage and replace haematopoiesis after an insult to the normal cells.

Copyright © 2000 S. Karger AG, Basel



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References

  1. Tichelli A, Gratwohl A, Wursch A, et al: Late haematological complications in severe aplastic anaemia. Br J Haematol 1988;69:413–418.
  2. Tichelli A, Gratwohl A, Nissen C, et al: Late clonal complications in severe aplastic anemia. Leuk Lymphoma 1994;12:167–175.

    External Resources

  3. Rosse WF, Ware RE: The molecular basis of paroxysmal nocturnal hemoglobinuria. Blood 1995;86:3277–3286.
  4. Luzzatto L, Bessler M: The dual pathogenesis of paroxysmal nocturnal hemoglobinuria. Curr Opin Hematol 1996;3:101–110.
  5. Schrezenmeier H, Hertenstein B, Wagner B, et al: A 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.
  6. Dunn DE, Tanawattanacharoen P, Boccuni P, et al: Paroxysmal nocturnal hemoglobinuria cells in patients with bone marrow failure syndromes (see comments). Ann Intern Med 1999;131:401–408.
  7. Fores R, Alcocer M, Diez Martin JL, et al: Flow cytometric analysis of decay-accelerating factor (CD55) on neutrophils from aplastic anaemia patients. Br J Haematol 1995;90:728–730.
  8. 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.
  9. Schubert J, Vogt HG, Zielinska Skowronek M, et al: Development of the glycosylphosphatitylinositol-anchoring defect characteristic for paroxysmal nocturnal hemoglobinuria in patients with aplastic anemia. Blood 1994;83:2323–2328.
  10. Tooze JA, Saso R, Marsh JC, et al: The novel monoclonal antibody By114 helps detect the early emergence of a paroxysmal nocturnal hemoglobinuria clone in aplastic anemia. Exp Hematol 1995;23:1484–1491.
  11. Nissen C, Tichelli A, Gratwohl A, et al: High incidence of transiently appearing complement-sensitive bone marrow precursor cells in patients with severe aplastic anemia: A possible role of high endogenous IL–2 in their suppression. Acta Haematol 1999;101:165–172.
  12. Rotoli B, Luzzatto L: Paroxysmal nocturnal haemoglobinuria. Baillières Clin Haematol 1989;2:113–138.

    External Resources

  13. Rotoli B, Bessler M, Alfinito F, et al: Membrane proteins in paroxysmal nocturnal haemoglobinuria. Blood Rev 1993;7:75–86.
  14. Young NS: The problem of clonality in aplastic anemia: Dr Dameshek’s riddle, restated. Blood 1992;79:1385–1392.
  15. Frickhofen N, Kaltwasser JP, Schrezenmeier H, et al: Treatment of aplastic anemia with antilymphocyte globulin and methylprednisolone with or without cyclosporine. N Engl J Med 1991;324:1297–1304.

    External Resources

  16. Bacigalupo A, Hows J, Gluckman E, et al: Bone marrow transplantation (BMT) versus immunosuppression for the treatment of severe aplastic anaemia (SAA): A report of the EBMT SAA working party. Br J Haematol 1988;70:177–182.

    External Resources

  17. Raghavachar A, Ganser A, Freund M, et al: Long-term interleukin–3 and intensive immunosuppression in the treatment of aplastic anemia. Cytokines Mol Ther 1996;215–223.
  18. Bessler M, Mason PJ, Hillmen P, et al: Paroxysmal nocturnal haemoglobinuria (PNH) is caused by somatic mutations in the PIG-A gene. EMBO J 1994;13:110–117.
  19. Bessler M, Mason P, Hillmen P, et al: Somatic mutations and cellular selection in paroxysmal nocturnal haemoglobinuria. Lancet 1994;343:951–953.
  20. Bessler M, Mason PJ, Hillmen P, et al: Mutations in the PIG-A gene causing partial deficiency of GPI-linked surface proteins (PNH II) in patients with paroxysmal nocturnal haemoglobinuria. Br J Haematol 1994;87:863–866.
  21. Miyata T, Takeda J, Iida Y, et al: The cloning of PIG-A, a component in the early step of GPI-anchor biosynthesis. Science 1993;259:1318–1320.
  22. Ostendorf T, Nischan C, Schubert J, et al: Heterogeneous PIG-A mutations in different cell lineages in paroxysmal nocturnal hemoglobinuria heterogeneous PIG-A mutations in different cell lineages in paroxysmal nocturnal hemoglobinuria. Blood 1995;85:1640–1646.
  23. Takeda J, Miyata T, Kawagoe K, et al: Deficiency of the GPI anchor caused by a somatic mutation of the PIG-A gene in paroxysmal nocturnal hemoglobinuria deficiency of the GPI anchor caused by a somatic mutation of the PIG-A gene in paroxysmal nocturnal hemoglobinuria. Cell 1993;73:703–711.
  24. Ware RE, Rosse WF, Howard TA: Mutations within the Piga gene in patients with paroxysmal nocturnal hemoglobinuria. Blood 1994;83:2418–2422.
  25. Yamada N, Miyata T, Maeda K, et al: Somatic mutations of the PIG-A gene found in Japanese patients with paroxysmal nocturnal hemoglobinuria. Blood 1995;85:885–892.
  26. Endo M, Ware RE, Vreeke TM, et al: Molecular basis of the heterogeneity of expression of glycosyl phosphatidylinositol anchored proteins in paroxysmal nocturnal hemoglobinuria. Blood 1996;87:2546–2557.
  27. Lin LI, Liu CH, Chen YC, et al: PIG-A gene mutations in four Taiwanese patients with paroxysmal nocturnal haemoglobinuria following aplastic anaemia. Br J Haematol 1997;97:286–292.
  28. Nafa K, Mason PJ, Hillmen P, et al: Mutations in the PIG-A gene causing paroxysmal nocturnal hemoglobinuria are mainly of the frameshift type. Blood 1995;86:4650–4655.
  29. Nagarajan S, Brodsky RA, Young NS, et al: Genetic defects underlying paroxysmal nocturnal hemoglobinuria that arises out of aplastic anemia. Blood 1995;86:4656–4661.
  30. Nishimura J, Inoue N, Wada H, et al: A patient with paroxysmal nocturnal hemoglobinuria bearing four independent PIG-A mutant clones. Blood 1997;89:3470–3476.
  31. Savoia A, Ianzano L, Lunardi C, et al: Identification of three novel mutations in the PIG-A gene in paroxysmal nocturnal haemoglobinuria (PNH) patients. Hum Genet 1996;97:45–48.
  32. Nakao S, Yamaguchi M, Takamatsu H, et al: Expansion of a paroxysmal nocturnal hemoglobinuria (PNH) clone after cyclosporine therapy for aplastic anemia/PNH syndrome (letter; comment). Blood 1992;80:2943–2944.
  33. Hillmen P, Hows JM, Luzzatto L: Two distinct patterns of glycosylphosphatidylinositol (GPI) linked protein deficiency in the red cells of patients with paroxysmal nocturnal haemoglobinuria. Br J Haematol 1992;80:399–405.
  34. van Kamp H, van Imhoff GW, de Wolf JT, et al: The effect of cyclosporine on haematological parameters in patients with paroxysmal nocturnal haemoglobinuria. Br J Haematol 1995;89:79–82.

    External Resources

  35. Dacie J: Paroxysmal nocturnal haemoglobinuria. Sangre 1980;25:890–895.
  36. Hillmen P, Bessler M, Luzzatto L, et al: Long-term follow-up of 80 patients with PNH: 11 of 32 patients surviving 10 years achieve spontaneous remission (abstract). Blood 1993;82 (suppl 1):310a.
  37. Hillmen P, Lewis SM, Bessler M, et al: Natural history of paroxysmal nocturnal hemoglobinuria. N Engl J Med 1995;333:1253–1258.
  38. Kusminsky GD, Barazzutti L, Korin JD, et al: Complete response to antilymphocyte globulin in a case of aplastic anemia-paroxysmal nocturnal hemoglobinuria syndrome (letter). Am J Hematol 1988;29:123.
  39. Nakakuma H, Nagakura S, Kawaguchi T, et al: Persistence of affected T lymphoctes in long-term clinical remission in paroxysmal nocturnal hemoglobinuria. Blood 1994;84:3925–3928.
  40. Iwamoto N, Kawaguchi T, Horikawa K, et al: Preferential hematopoiesis by paroxysmal nocturnal hemoglobinuria clone engrafted in SCID mice. Blood 1996;87:4944–4948.
  41. Kawagoe K, Kitamura D, Okabe M, et al: Glycosylphosphatidylinositol-anchor-deficient mice: Implications for clonal dominance of mutant cells in paroxysmal nocturnal hemoglobinuria. Blood 1996;87:3600–3606.
  42. Keller P, Tremml G, Rosti V, et al: X inactivation and somatic cell selection rescue female mice carrying a Piga-null mutation. Proc Natl Acad Sci USA 1999;96:7479–7483.
  43. Maciejewski JP, Sloand EM, Sato T, et al: Impaired hematopoiesis in paroxysmal nocturnal hemoglobinuria / aplastic anemia is not associated with a selective proliferative defect in the glycosylphosphatidylinositol-anchored protein-deficient clone. Blood 1997;89:1173–1181.
  44. Brett SJ, Baxter G, Cooper H, et al: Emergence of CD52-, glycosylphosphatidylinositol-anchor-deficient lymphocytes in rheumatoid arthritis patients following Campath-1 treatment. Int Immunol 1996;8:325–334.

    External Resources

  45. Hertenstein B, Wagner B, Bunjes D, et al: Emergence of CD52-, phosphatidylinositolglycan-anchor-deficient T lymphocytes after in vivo application of Campath-1H for refractory B-cell Non-Hodgkin Lymphoma Emergence of CD52-, phosphatidylinositolglycan-anchor-deficient T lymphocytes after in vivo application of Campath-1H for refractory B-cell non-Hodgkin lymphoma. Blood 1995;86:1487–1492.


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