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Paroxysmal Nocturnal Hemoglobinuria pp 55–65Cite as

Animal Models of Paroxysmal Nocturnal Hemoglobinuria

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Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) is caused by the somatic mutation of the PIGA gene of one or several hematopoietic stem cells, but how these stem cells acquire dominance to full expansion is not clearly elucidated. We and other groups have generated and studied several animal models to clarify this unknown. The first-generation models were simple Piga knockout mice that were shown to be lethal. The second-generation models were conditional Piga knockout mice using the Cre/loxP system, which indicated that a Piga mutation alone does not account for the dominance of the mutant stem cells and that other factors are involved in pathogenesis of PNH. From the observation of PNH clones in aplastic anemia patients, we hypothesize that immunological selection and additional abnormality, leading to benign tumorlike proliferation, would be necessary for clonal expansion of GPI-negative cells in addition to the PIGA mutation. Immunological selection was experimentally proven by our model mice in combination with bone marrow chimera. From the analysis of the PNH patients with a chromosome 12 abnormality, we identified the candidate gene, HMGA2, for the benign tumorlike proliferation. HMGA2-expressing hematopoietic stem cells showed increased proliferation in mice. Although the expression of HMGA2 in pluripotent stem cells requires testing, HMGA2 expression was found to increase in peripheral blood cells for 75 % of PNH patients examined.

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Author information

Authors and Affiliations

  1. Department of Immunoregulation, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka, 565-0871, Japan

    Yoshiko Murakami M.D., Ph.D.

  2. Department of Immunoglycobiology, WPI Immunology Frontier Research Center, Osaka University, 3-1 Yamadaoka, Suita, Osaka, 565-0871, Japan

    Yoshiko Murakami M.D., Ph.D.

  3. Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, 565-0871, Osaka, Japan

    Taroh Kinoshita

  4. WPI Immunology Frontier Research Center, Osaka University, 3-1 Yamadaoka, Suita, 565-0871, Osaka, Japan

    Taroh Kinoshita

Authors
  1. Yoshiko Murakami M.D., Ph.D.
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  2. Taroh Kinoshita
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Corresponding author

Correspondence to Yoshiko Murakami M.D., Ph.D. .

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Editors and Affiliations

  1. Department of Hematology and Ocology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan

    Yuzuru Kanakura

  2. Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan

    Taroh Kinoshita

  3. Dept of Hematology and Ocology, Osaka University Dept of Hematology and Ocology, Suita, Osaka, Japan

    Jun-ichi Nishimura

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Murakami, Y., Kinoshita, T. (2017). Animal Models of Paroxysmal Nocturnal Hemoglobinuria. In: Kanakura, Y., Kinoshita, T., Nishimura, Ji. (eds) Paroxysmal Nocturnal Hemoglobinuria. Springer, Tokyo. https://doi.org/10.1007/978-4-431-56003-6_3

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  • DOI: https://doi.org/10.1007/978-4-431-56003-6_3

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