International Journal of Hematology

, Volume 73, Issue 2, pp 206–212 | Cite as

Acute Myelogenous Leukemia WithPIG-A Gene Mutation Evolved from Aplastic Anemia—Paroxysmal Nocturnal Hemoglobinuria Syndrome

  • Hideo Tanaka
  • Nobutaka Imamura
  • Nobuo Oguma
  • Takahiro Shintani
  • Kimio Tanaka
  • Hideo Hyodo
  • Kenji Oda
  • Akiro Kimura
Case Report


We report a patient with aplastic anemia (AA)—paroxysmal nocturnal hemoglobinuria (PNH) syndrome who developed acute myelogenous leukemia (AML). Flow cytometric analysis showed that the leukemic cells in the bone marrow lacked CD59 antigen on their surface and were positive for P-glycoprotein. Heteroduplex and single-strand conformation polymorphism analysis followed by sequencing of the leukemic cells in the bone marrow disclosed 1 frameshift-type mutation in exon 2 of the phosphatidylinositol glycan-class A (PIG-A) gene, which deductively produces truncated PIG-A protein. These findings provide direct evidence that the leukemic cells evolved from the affected PNH clone. Cytogenetic analysis in the bone marrow in each stage of AA-PNH, AML, and at relapse of AML showed normal, −7, and −7 plus −20, respectively, showing evidence of a clonal evolution. Because complete remission of AML was not achieved by intensive chemotherapies, allogeneic peripheral blood stem cell transplantation (PBSCT) from the patient’s HLA-matched sister was performed successfully with recovery of CD59 antigen on bone marrow hematopoietic cells; however, leukemia relapsed 4 months after PBSCT. Leukemia derived from PNH may be resistant to intensive chemotherapy, and a highly myeloablative regimen may be required for stem cell transplantation to eradicate the PNH-derived leukemia clone.

Key words

PNH Leukemia Chromosome PBSCT P-glycoprotein 


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  1. 1.
    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.Cell. 1993;73:703–711.CrossRefPubMedGoogle Scholar
  2. 2.
    Kinoshita T, Inoue N, Takeda J. Defective glycosyl phosphatidylinositol anchor synthesis and paroxysmal nocturnal hemoglobinuria.Adv Immunol. 1995;60:57–103.CrossRefPubMedGoogle Scholar
  3. 3.
    Nishimura J, Murakami Y, Kinoshita T. Paroxysmal nocturnal hemoglobinuria: an acquired genetic disease.Am J Hematol. 1999;62:175–182.CrossRefPubMedGoogle Scholar
  4. 4.
    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.CrossRefPubMedGoogle Scholar
  5. 5.
    Harris JW, Koscick R, Lazarus HM, Eshleman JR, Medof ME. Leukemia arising out of paroxysmal nocturnal hemoglobinuria.Leuk Lymphoma. 1999;32:401–426.CrossRefPubMedGoogle Scholar
  6. 6.
    Devine DV, Gluck WL, Rosse WF, Weinberg JB. Acute myeloblastic leukemia in paroxysmal nocturnal hemoglobinuria: evidence of evolution from the abnormal paroxysmal nocturnal hemoglobinuria clone.J Clin Invest. 1987;79:314–317.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Nakahata J, Takahashi M, Fuse I, et al. Paroxysmal nocturnal hemoglobinuria with myelofibrosis: progression to acute myeloblastic leukemia.Leuk Lymphoma. 1993;12:137–142.CrossRefPubMedGoogle Scholar
  8. 8.
    Shichishima T, Terasawa T, Hashimoto C, et al. Discordant and heterogeneous expression of GPI-anchored membrane proteins on leukemic cells in a patient with paroxysmal nocturnal hemoglobinuria.Blood. 1993;81:1855–1862.PubMedGoogle Scholar
  9. 9.
    van Kamp H, Smit J, van den Berg E, Ruud Halie M, Vellenga E. Myelodysplasia following paroxysmal nocturnal hemoglobinuria: evidence for the emergence of a separate clone.Br J Haematol. 1994;87:399–400.CrossRefPubMedGoogle Scholar
  10. 10.
    Jin JY, Tooze JA, Marsh JCW, Matthey F, Gordon-Smith EC. Myelodysplasia following aplastic anaemia-paroxysmal nocturnal haemoglobinuria syndrome after treatment with immunosuppression and G-CSF: evidence for the emergence of a separate clone.Br J Haematol. 1996;94:510–512.CrossRefPubMedGoogle Scholar
  11. 11.
    Mortazavi Y, Tooze J, Gordon-Smith E, Rutherford T. N-RAS gene mutation in patients with aplastic anemia/paroxysmal nocturnal hemoglobinuria during evolution to clonal disease.Blood. 1999;95:646–650.Google Scholar
  12. 12.
    Imamura N, Kusunoki Y, Kawa-Ha K, et al. Aggressive natural killer cell leukemia/lymphoma: report of four cases and review of the literature: possible existence of a new clinical entity originating from the third lineage of lymphoid cells.Br J Haematol. 1990;75:49–59.CrossRefPubMedGoogle Scholar
  13. 13.
    Imamura N, Kimura A. Neutropenia among survivors of atomic bomb explosion.Lancet. 2000;355:117.CrossRefPubMedGoogle Scholar
  14. 14.
    Imamura N, Tanaka R, Kajihara H, Kuramoto A. Analysis of peroxidase-negative acute unclassifiable leukemias by monoclonal antibodies, I: acute myelogenous leukemia and acute myelomonocytic leukemia.Eur J Haematol. 1988;41:420–428.CrossRefPubMedGoogle Scholar
  15. 15.
    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.PubMedGoogle Scholar
  16. 16.
    Stafford HA, Nagarajan S, Weinberg JB, Medof ME. PIG-A, DAF and proto-oncogene expression in paroxysmal nocturnal haemoglobinuria-associated acute myelogenous leukaemia blasts.Br J Haematol. 1995;89:72–78.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Nafa K, Bessler M, Deeg H, Luzzatto L. New somatic mutation in the PIG-A gene emerges at relapse of paroxysmal nocturnal hemoglobinuria.Blood. 1998;92:3422–3427.PubMedPubMedCentralGoogle Scholar
  18. 18.
    Imashuku S, Hibi S, Kataoka-Morimoto Y, et al. Myelodysplasia and acute myeloid leukaemia in case of aplastic anaemia and congenital neutropenia following G-CSF administration.Br J Haematol. 1995;89:188–190.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Szer J, Deeg H, Witherspoon R, et al. Long-term survival after transplantation for paroxysmal nocturnal hemoglobinuria with aplastic anemia.Ann Intern Med. 1984;101:193–195.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Antin J, Ginsberg D, Smith B, Nathan D, Orkin S, Rapperport J. Bone marrow transplantation for paroxysmal nocturnal hemoglobinuria: eradication of the PNH clone and documentation of complete lymphohematopoietic engraftment.Blood. 1985;66:1247–1250.PubMedGoogle Scholar
  21. 21.
    Kolb H, Holler E, Bender-Gotze C, Walther U. Myeloablative conditioning for marrow transplantation in myelodysplastic syndromes and paroxysmal nocturnal haemoglobinuria.Bone Marrow Transplant. 1989;4:29–34.PubMedGoogle Scholar
  22. 22.
    Bemba M, Guardiola P, Garderet L, et al. Bone marrow transplantation for paroxysmal nocturnal haemoglobinuria.Br J Haematol. 1999;105:366–368.CrossRefPubMedGoogle Scholar
  23. 23.
    Kawahara K, Witherspoon RP, Storb R. Marrow transplantation for paroxysmal nocturnal hemoglobinuria.Am J Hematol. 1992;39: 283–288.CrossRefPubMedGoogle Scholar
  24. 24.
    Raiola A, Van Lint M, Lamparelli T, et al. Bone marrow transplantation for paroxysmal nocturnal hemoglobinuria.Haematologica. 2000;85:59–62.PubMedGoogle Scholar
  25. 25.
    Saso R, Marsh J, Cevreska L, et al. Bone marrow transplants for paroxysmal nocturnal haemoglobinuria.Br J Haematol. 1999;104: 392–396.CrossRefPubMedGoogle Scholar
  26. 26.
    Cornelis F, Montfort L, Osselaer J, et al. Acute leukemia in paroxysmal nocturnal haemoglobinuria: case report and review of the literature.Hematol Cell Ther. 1996;1996:285–288.CrossRefGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2001

Authors and Affiliations

  • Hideo Tanaka
    • 1
  • Nobutaka Imamura
    • 1
  • Nobuo Oguma
    • 2
  • Takahiro Shintani
    • 2
  • Kimio Tanaka
    • 2
  • Hideo Hyodo
    • 1
  • Kenji Oda
    • 1
  • Akiro Kimura
    • 1
  1. 1.Department of Hematology and OncologyResearch Institute for Radiation Biology and Medicine, Hiroshima UniversityHiroshimaJapan
  2. 2.Department of Molecular CytogeneticsResearch Institute for Radiation Biology and Medicine, Hiroshima UniversityHiroshimaJapan

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