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Deletions of Xp22.2 including PIG-A locus lead to paroxysmal nocturnal hemoglobinuria

Leukemia volume 25, pages 379–382 (2011)Cite this article

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Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematopoietic stem cell disorder characterized by a global deficiency of glycosylphospatidyl inositol-anchored proteins (GPI-APs) on the membrane of all cell types derived from the affected stem cell.1 The corresponding clinical phenotype results from the deficiency of GPI-AP on individual cells, and includes a triad of intravascular hemolytic anemia, propensity for thrombosis and bone marrow failure inherently linked to the properties of the affected stem cell. Although the PNH phenotype is non-malignant, outgrowth of GPI-AP (–) clones is mediated by a selective advantage in the context of a permissive condition, such as autoimmune-mediated bone marrow suppression as seen in aplastic anemia.2 The GPI-AP (–) phenotype results from mutations of the PIG-A gene, located at Xp22.2, which participates in GPI synthesis.3 Because the gene is X-linked, a single frame-shift or missense inactivating mutation results in loss of GPI-AP expression on the cell surface and because of the X-chromosome inactivation, the frequency of PNH is similar in men and women.

New cytogenetic technologies, such as single-nucleotide polymorphism array-based karyotyping, show superb resolution allowing for detection of submicroscopic chromosomal defects not seen on metaphase spreads.4 We have systematically applied this technology to identify clonal aberrations in patients with various forms of bone marrow failure.5 During this molecular screen, a microdeletion of Xp22.2, encompassing the PIG-A locus, was found in three patients with PNH. We have shown that in addition to PIG-A mutations, PNH results from clonal deletion of chromosomal material, likely leading to the same selective clonal advantage as hypomorphic mutation of the PIG-A gene.

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Acknowledgements

This work was supported in part by RO1HL-082983, U54 RR019391 K24 HL-077522 and by grant from AA&MDS International Foundation and Robert Duggan Charitable Fund (JPM).

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Author notes

  1. C L O'Keefe and C Sugimori: These authors contributed equally to this work.

  2. P K Epling-Burnette and J P Maciejewski: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Translational Hematology and Hematopoiesis, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA

    C L O'Keefe, M Clemente & J P Maciejewski

  2. Immunology Program and Malignant Hematology Division, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA

    C Sugimori, K Shain, A List & P K Epling-Burnette

  3. Department of Hematologic Oncology and Blood Disorders, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA

    M Afable

  4. Division of Hematology, NYU School of Medicine and the New York VA Medical Center, New York, NY, USA

    D J Araten & J P Maciejewski

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  1. C L O'Keefe
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Correspondence to C L O'Keefe.

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O'Keefe, C., Sugimori, C., Afable, M. et al. Deletions of Xp22.2 including PIG-A locus lead to paroxysmal nocturnal hemoglobinuria. Leukemia 25, 379–382 (2011). https://doi.org/10.1038/leu.2010.274

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