Abstract
PNH is characterized by expansion of one or more stem cell clones with a PIG-A mutation, which causes a severe deficiency in the expression of glycosylphosphatidylinositol (GPI)-anchored proteins. There is evidence that the expansion of PIG-A mutant clones is concomitant with negative selection against PIG-A wild-type stem cells by an aplastic marrow environment. We studied 36 patients longitudinally by serial flow cytometry, and we determined the proportion of PNH red cells and granulocytes over a period of 1–6 years. We observed expansion of the PNH blood cell population(s) (at a rate of over 5% per year) in 12 out of 36 patients; in all other patients the PNH cell population either regressed or remained stable. The dynamics of the PNH cell population could not be predicted by clinical or hematologic parameters at presentation. These data indicate that in most cases the PNH cell expansion has already run its course by the time of diagnosis. In addition, since in most cases no further expansion takes place, we can infer that the tendency to overgrow normal cells is not an intrinsic property of the PNH clone.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Oni S, Osunkoya B, Luzzatto L . Paroxysmal nocturnal hemoglobinuria: evidence for monoclonal origin of abnormal red cells Blood 1970 36: 145–152
Parker CJ . Hemolysis in PNH In: Young NS, Moss J (eds) PNH and the GPI-linked Proteins Academic Press: San Diego 2000 pp 49–100
Rosse WF, Ware R . The molecular basis of paroxysmal nocturnal hemoglobinuria Blood 1995 9: 3277–3286
Rosti V . The molecular basis of paroxysmal nocturnal hemoglobinuria Haematologica 2000 85: 82–87
Miyata T, Takeda J, Iida Y, Yamada N, Inoue N, Takahashi M . Maeda K, Kitani T, Kinoshita T. The cloning of PIG-A, a component in the early step of GPI-anchor biosynthesis Science 1993 2591: 318–320
Hillmen P, Bessler M, Mason PJ, Watkins WM, Luzzatto L . Specific defect in N-acetylglucosamine incorporation in the biosynthesis of the glycosylphosphatidylinositol anchor in cloned cell lines from patients with paroxysmal nocturnal hemoglobinuria Proc Natl Acad Sci USA 1993 90: 5272–5276
Miyata T, Yamada N, Iida Y, Nishimura J, Takeda J, Kitani T, Kinoshita T . Abnormalities of PIG-A transcripts in granulocytes from patients with paroxysmal nocturnal hemoglobinuria N Engl J Med 1994 330: 249–255
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 USA 1999 96: 5209–5214
Dacie JV, Lewis SM . Paroxysmal nocturnal hemoglobinuria; clinical manifestations, haematology, and nature of the disease. 1 Series Haematologica 1972 5: 2–23
Dunn DE, Liu JM, Young NS . Paroxysmal nocturnal hemoglobinuria In: Young, NS (ed) Bone Marrow Failure Syndromes WB Saunders: Philadelphia 2000 pp 99–121
Luzzatto L, Bessler M, Rotoli B . Somatic mutations in paroxysmal nocturnal hemoglobinuria: a blessing in disguise? Cell 1997 88: 1–4
Rotoli B, Luzzatto L . Paroxysmal nocturnal hemoglobinuria Baillière's 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
Rotoli B, Robledo R, Luzzatto L . Decreased number of circulating BFU-Es in paroxysmal nocturnal hemoglobinuria Blood 1982 60: 157–159
Stoppa AM, Vey N, Sainty D, Arnoulet C, Camerlo J, Cappiello MA, Gastaut JA, Maraninchi D . Correction of aplastic anemia complicating paroxysmal nocturnal hemoglobinuria: absence of eradication of the PNH clone and dependence of response on cyclosporin A administration Br J Haematol 1996 93: 42–44
Karadimitris A, Manavalan JS, Thaler HT, Notaro R . Araten DJ, Nafa K. Roberts IA, Weksler ME, Luzzatto L. Abnormal T-cell repertoire is consistent with immune process underlying the pathogenesis of paroxysmal nocturnal hemoglobinuria Blood 2000 96: 2613–2620
Araten DJ, Swirsky D, Karadimitris A, Notaro R . Nafa K, Bessler M, Thaler HT, Castro-Malaspina H, Childs BH, Boulad F, Weiss M, Anagnostopoulos N, Kutlar A, Savage DG, Maziarz RT, Jhanwar S, Luzzatto L. Cytogenetic and morphological abnormalities in paroxysmal nocturnal haemoglobinuria Br J Haematol 2001 115: 360–368
Dunn DE, Tanawattanacharoen P, Boccuni P, Nagakura S, Green SW, Kirby MR, Kumar MS, Rosenfeld S, Young NS . Paroxysmal nocturnal hemoglobinuria cells in patients with bone marrow failure syndromes Ann Intern Med 1999 131: 401–408
Iwanaga M, Furukawa K, Amenomori T, Mori H . Nakamura H, Fuchigami K, Kamihira S, Nakakuma H, Tomonaga M. Paroxysmal nocturnal haemoglobinuria clones in patients with myelodysplastic syndromes Br J Haematol 1998 102: 465–474
Harris JW, Koscick R, Lazarus HM, Eshleman JR, Medof ME . Leukemia arising out of paroxysmal nocturnal hemoglobinuria Leuk Lymphoma 1999 32: 401–426
Catalano L, Selleri C, Califano C, Luciano L, Volpicelli M, Rocco S, Varriale G, Ricci P, Rotoli B . Prolonged response to cyclosporin-A in hypoplastic refractory anemia and correlation with in vitro studies Haematologica 2000 85: 133–138
Maciejewski JP, Rivera C, Kook H, Dunn D, Young NS . Relationship between bone marrow failure syndromes and the presence of glycosylphosphatidyl inositol-anchored protein-deficient clones Br J Haematol 2001 115: 1015–1022
Hillmen P, Lewis SM, Bessler M, Luzzatto L, Dacie JV . Natural history of paroxysmal nocturnal hemoglobinuria N Engl J Med 1995 33: 1253–1258
Mahbub B, Nishimura J, Kitani T, Kitano K . Decay accelerating factor deficient erythrocytes during the long-term clinical course of patients with paroxysmal nocturnal hemoglobinuria Acta Haematol 1995 93: 91–97
Schrezenmeier H, Hildebrand A, Rojewski M, Hacker H, Raghavachar A . Paroxysmal nocturnal haemoglobinura: a replacement of haematopoietic tissue? Acta Haematol 2000 103: 41–48
Yamaguchi M, Machii T, Azenishi Y, Nishimura J, Shibano M, Kanakura Y, Kitani T . Detection of small populations of CD59-deficient erythrocytes in patients with aplastic anemia or myelodysplastic syndrome and normal individuals Blood Cells Mol Dis 2000 26: 247–254
Wang H, Chuhjo T, Yamazaki H, Shiobara S, Teramura M, Mizoguchi H, Nakao S . Relative increase of granulocytes with a paroxysmal nocturnal haemoglobinuria phenotype in aplastic anemia patients: the high prevalence at diagnosis Eur J Haematol 2001 66: 200–205
Luzzatto L . Paroxysmal murine hemoglobinuria (?): a model for human PNH Blood 1999 94: 2941–2944
Karadimitris A, Luzzatto L . The cellular pathogeneisis of paroxysmal nocturnal haemoglobinuria Leukemia 2001 15: 1148–1152
Bessler M, Mason P, Hillmen P, Luzzatto L . Somatic mutations and cellular selection in paroxysmal nocturnal haemoglobinuria Lancet 1994 343: 951–953
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
Antin JH, Ginsburg D, Smith BR, Nathan DG, Orkin SH, Rappeport JM . Bone marrow transplantation for paroxysmal nocturnal hemoglobinuria: eradication of the PNH clone and documentation of complete lymphohematopoietic engraftment Blood 1985 66: 1247–1250
Paquette RL, Yoshimura R, Veiseh C, Kunkel L, Gajewski J, Rosen PJ . Clinical characteristics predict response to anithymocyte globulin in paroxysmal nocturnal haemoglobinuria Br J Haematol 1997 96: 92–97
Acknowledgements
We would like to thank Mary Ang, Nimfa Boma, Ruth Rose, Jane Rueda, Nadia Soukhram, and Diane Tabarini for their technical assistance. This work was supported by the Aplastic Anemia Foundation of America New Researcher Award, the Norman and Rosita Winston and the Charles A Dana Foundations, and the National Institute of Health 5RO1 HL56778-03 Grant and Associazione Italiana per la Ricerca sul Cancro.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Araten, D., Bessler, M., McKenzie, S. et al. Dynamics of hematopoiesis in paroxysmal nocturnal hemoglobinuria (PNH): no evidence for intrinsic growth advantage of PNH clones. Leukemia 16, 2243–2248 (2002). https://doi.org/10.1038/sj.leu.2402694
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.leu.2402694
Keywords
This article is cited by
-
Analysis of TET2 mutations in paroxysmal nocturnal hemoglobinuria (PNH)
Experimental Hematology & Oncology (2019)
-
The in vitro PIG-A gene mutation assay: mutagenicity testing via flow cytometry based on the glycosylphosphatidylinositol (GPI) status of TK6 cells
Archives of Toxicology (2015)
-
The clinical relevance of minor paroxysmal nocturnal hemoglobinuria clones in refractory cytopenia of childhood: a prospective study by EWOG-MDS
Leukemia (2014)
-
Stochastic dynamics and the evolution of mutations in stem cells
BMC Biology (2011)
-
Pathogenesis of Selective Expansion of PNH Clones
International Journal of Hematology (2003)