Blood Journal
Leading the way in experimental and clinical research in hematology

Molecular basis of clonal expansion of hematopoiesis in 2 patients with paroxysmal nocturnal hemoglobinuria (PNH)

  1. Norimitsu Inoue,
  2. Tomohisa Izui-Sarumaru,
  3. Yoshiko Murakami,
  4. Yuichi Endo,
  5. Jun-Ichi Nishimura,
  6. Ken Kurokawa,
  7. Maki Kuwayama,
  8. Hiroaki Shime,
  9. Takashi Machii,
  10. Yuzuru Kanakura,
  11. Gabrielle Meyers,
  12. Carl Wittwer,
  13. Zhong Chen,
  14. William Babcock,
  15. Debra Frei-Lahr,
  16. Charles J. Parker, and
  17. Taroh Kinoshita
  1. From the Department of Molecular Genetics, Osaka Medical Center for Cancer, Japan; the Department of Immunoregulation, Research Institute for Microbial Diseases, Osaka University, Japan; the Department of Immunology, Fukushima Medical University, Japan; the Department of Medicine, Duke University Medical Center, Durham, NC; the Genome Information Research Center, Osaka University, Japan; the Department of Hematology and Oncology, Osaka University School of Medicine, Japan; the Department of Medicine, Division of Hematology and Bone Marrow Transplant, University of Utah School of Medicine, Salt Lake City, UT; the Department of Medicine, Hematology/Oncology Section, George E. Whalen Veterans Administration (VA) Medical Center, Salt Lake City, UT; the Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT; the Division of Medical Genetics, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT; the Department of Medicine, Division of Hematology/Oncology, Baptist Medical Center, Columbia, SC; the Department of Medicine, Division of Hematology, Medical University of South Carolina, Charleston, SC; and the Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Saitama, Japan.

Abstract

Somatic mutation of PIGA in hematopoietic stem cells causes deficiency of glycosyl phosphatidylinositol–anchored proteins in paroxysmal nocturnal hemoglobinuria (PNH) that underlies the intravascular hemolysis but does not account for expansion of the PNH clone. Immune mechanisms may mediate clonal selection but appear insufficient to account for the clonal dominance necessary for PNH to become clinically apparent. Herein, we report 2 patients with PNH whose PIGA-mutant cells had a concurrent, acquired rearrangement of chromosome 12. In both cases, der(12) had a break within the 3′ untranslated region of HMGA2, the architectural transcription factor gene deregulated in many benign mesenchymal tumors, that caused ectopic expression of HMGA2 in the bone marrow. These observations suggest that aberrant HMGA2 expression, in concert with mutant PIGA, accounts for clonal hematopoiesis in these 2 patients and suggest the concept of PNH as a benign tumor of the bone marrow.

  • Submitted May 23, 2006.
  • Accepted August 8, 2006.
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