Pathogenesis of Clonal Dominance in PNH: Growth Advantage in PNH

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematopoietic disorder characterized by the clonal expansion of glycosylphosphatidylinositol (GPI)-deficient hematopoietic stem cells (HSCs). Although the deficiency in GPI caused by a somatic mutation in phosphatidylinositol glycan-class A (PIGA) can clearly account for the characteristic manifestation of intravascular hemolysis induced by complement attack in patients with PNH, additional abnormalities must be involved in the clonal expansion of GPI-deficient HSCs. Several reports have shown additional abnormalities predicted to be involved in the growth advantage of GPI-deficient HSCs in PNH. One of the best candidates is HMGA2, a gene encoding an architectural transcriptional regulator that is deregulated in many benign mesenchymal tumors. The aberrant expression of HMGA2 in PNH clones suggests that PNH may be viewed as a benign tumor of bone marrow cells. WT1 transcript upregulation and JAK2 p.V617F somatic mutation, observed in the other hematopoietic malignancies such as myeloproliferative neoplasms and myelodysplastic syndrome, have also been observed in some patients with PNH. In a recent whole-exome sequencing analysis, an average of two additional somatic mutations were observed in patients with PNH, and somatic mutations in many genes identified in other hematopoietic malignancies have been found. No gene abnormality has been found to be common to all patients with PNH. Further epigenetic and genetic analyses are necessary to clarify the general molecular mechanism involved in the expansion of PNH clones.