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How do PIG-A mutant paroxysmal nocturnal hemoglobinuria stem cells achieve clonal dominance? Expert Rev. Hematol. 2(4), 353–356 (2009)
“The mechanism of clonal expansion continues to be an
Robert A Brodsky,
important question in the pathogenesis of paroxysmal nocturnal hemoglobinuria.”
MD Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Ross Research Building, Room 1025, 720 Rutland Avenue, Baltimore, MD 21205-2196, USA Tel.: +1 410 502 2546 Fax: +1 410 955 0185
[email protected]
Function & consequence of PIG-A mutations
Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal hematopoietic stem cell disease that can present with bone marrow failure, hemolytic anemia and thrombosis [1,2] . The disease originates from a multipotent hematopoietic stem cell that acquires a PIG-A mutation [3,4] . Expansion and differentiation of the PIG-A mutant stem cell leads to clinical manifestations of the disease. The PIG-A gene product is required for the biosynthesis of glycophosphatidylinositol (GPI) anchors, a glycolipid moiety that attaches dozens of proteins to the plasma membrane of cells. Consequently, the PNH stem cell and all of its progeny have a deficiency or absence of GPI-anchored proteins (GPI-APs). Two of these GPI-APs, CD55 and CD59, are complement regulatory proteins that are fundamental to the pathophysiology of the disease [5,6] . CD55 inhibits C3 convertases and CD59 blocks formation of the membrane attack complex. The loss of these complement regulatory proteins renders PNH erythrocytes susceptible to intravascular and extravascular hemolysis, but it is the intravascular hemolysis that contributes to most of the morbidity and mortality of the disease [7] . Fortunately, effective treatment with a monoclonal antibody (eculizumab) that inhibits terminal complement activation is now available for PNH patients [8–10] .
human PIG-A gene contains six exons, five introns, and codes for a protein that contains 484 amino acids (60 kDa). There is a single copy of the gene located on the short arm of the X chromosome (Xp22.1). A wide range of somatic mutations interspersed throughout the entire coding region of the PIG-A gene have been described in PNH patients. The initial evidence that PNH originates from a multipotent hematopoietic stem cell was derived from glucose 6-phosphate dehydrogenase studies on the red blood cells of women with PNH [11] . Subsequently, flow cytometric analyses revealed that all hematopoietic lineages – myeloid, erythroid and lymphoid – contained GPI-APdeficient cells. Moreover, these cells have matching PIG-A mutations, confirming that they must have arisen from a common ancestral cell [12,13] . PIG-A mutations in healthy controls
Interestingly, PIG-A mutant blood cells are also readily detected in the blood and bone marrow of healthy control subjects at a frequency of roughly one in 50,000 (0.002%) [13–15] . Meticulous molecular and statistical analysis reveals that unlike PIG-A mutations in PNH, most, if not all, of these mutations arise from colony forming cells rather than multipotent hematopoietic stem cells [13,16] . Thus, one reason why healthy controls harbor PIG-A mutations but seldom develop PNH is that PIG-A mutations in PNH these mutations – unlike PIG-A mutations PIG-A mutations in PNH arise from a in PNH patients – arise from cells that lack multipotent hematopoietic stem cell. The self-renewal capacity.
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10.1586/EHM.09.35
© 2009 Expert Reviews Ltd
ISSN 1747-4086
353
Editorial
Brodsky
PIG-A mutations in the setting of bone marrow failure
Small-to-moderate PNH populations (≥0.1%) are found in up to 60% of patients with acquired aplastic anemia, suggestive of a pathophysiologic link between these disorders [17–20] . Typically, fewer than 20% GPI-AP-deficient granulocytes are detected in aplastic anemia patients at diagnosis, but occasionally patients have larger populations [19] . PIG-A gene sequencing of the PNHlike cells from aplastic anemia patients reveals that they are clonal and are present in multiple lineages demonstrating that they also arise from multipotent hematopoietic stem cells [21] . Moreover, many of these patients experience expansion of the PIG-A mutant clone and progress to clinical PNH. Minor populations of GPI-AP-deficient cells (often
