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<p>Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by complement-dependent intravascular hemolysis and thrombosis as well as bone marrow failure. Complement dysregulation occurs as a result of defective cell surface expression of two glycosylphosphatidylinositol (GPI)-anchored complement regulators, decay-accelerating factor/CD55 and CD59, caused by somatic mutation of the phosphatidylinositol glycan anchor biosynthesis class A gene (<i>PIGA</i>). Somatic loss-of-function mutation of <i>PIGA</i> generates GPI-anchor-defective hematopoietic stem cell clones, the expansion of which results in large numbers of abnormal erythrocytes, platelets, and other blood cells. The clonal expansion of <i>PIGA</i> mutant hematopoietic stem cells is thought to be mediated by an autoimmune mechanism that suppresses or eliminates normal hematopoietic stem cells while sparing GPI-defective stem cell clones under bone marrow failure environments, the acquisition of a growth phenotype, or both of these mechanisms. This review examines current knowledge and views about the clonal expansion mechanism.</p>

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Clonal expansion mechanisms in paroxysmal nocturnal hemoglobinuria

  • 期刊论文

  • 发表日期：

    2026年2月9日

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  • Taroh Kinoshita

摘要

Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by complement-dependent intravascular hemolysis and thrombosis as well as bone marrow failure. Complement dysregulation occurs as a result of defective cell surface expression of two glycosylphosphatidylinositol (GPI)-anchored complement regulators, decay-accelerating factor/CD55 and CD59, caused by somatic mutation of the phosphatidylinositol glycan anchor biosynthesis class A gene (PIGA). Somatic loss-of-function mutation of PIGA generates GPI-anchor-defective hematopoietic stem cell clones, the expansion of which results in large numbers of abnormal erythrocytes, platelets, and other blood cells. The clonal expansion of PIGA mutant hematopoietic stem cells is thought to be mediated by an autoimmune mechanism that suppresses or eliminates normal hematopoietic stem cells while sparing GPI-defective stem cell clones under bone marrow failure environments, the acquisition of a growth phenotype, or both of these mechanisms. This review examines current knowledge and views about the clonal expansion mechanism.