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

Norimitsu Inoue, Tomohisa Izui-Sarumaru, Yoshiko Murakami, Yuichi Endo, Jun Ichi Nishimura, Ken Kurokawa, Maki Kuwayama, Hiroaki Shime, Takashi Machii, Yuzuru Kanakura, Gabrielle Meyers, Carl Wittwer, Zhong Chen, William Babcock, Debra Frei-Lahr, Charles J. Parker, Taroh Kinoshita

    Research output: Contribution to journalArticle

    100 Scopus citations

    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.

    Original languageEnglish (US)
    Pages (from-to)4232-4236
    Number of pages5
    JournalBlood
    Volume108
    Issue number13
    DOIs
    StatePublished - Dec 15 2006

    ASJC Scopus subject areas

    • Biochemistry
    • Immunology
    • Hematology
    • Cell Biology

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  • Cite this

    Inoue, N., Izui-Sarumaru, T., Murakami, Y., Endo, Y., Nishimura, J. I., Kurokawa, K., Kuwayama, M., Shime, H., Machii, T., Kanakura, Y., Meyers, G., Wittwer, C., Chen, Z., Babcock, W., Frei-Lahr, D., Parker, C. J., & Kinoshita, T. (2006). Molecular basis of clonal expansion of hematopoiesis in 2 patients with paroxysmal nocturnal hemoglobinuria (PNH). Blood, 108(13), 4232-4236. https://doi.org/10.1182/blood-2006-05-025148