Somatic mutations and clonal expansions in paroxysmal nocturnal hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal hematopoietic stem cell disorder caused by a mutation of the X-linked PIGA gene, resulting in a deficient expression of glycosylphosphatidylinositol (GPI)-anchored proteins. While large clonal expansions of GPI(-) cells cause hemolytic symptoms, tiny GPI(-) cell populations can be found in healthy individuals and remain miniscule throughout life. The slight expansion of PNH clones often occurs in patients with acquired aplastic anemia (AA), an autoimmune bone marrow (BM) failure caused by autoreactive cytotoxic T lymphocyte attack on hematopoietic stem and progenitor cells (HSPCs). The presence of PNH clones is thought to represent the immune pathophysiology of BM failure and be derived from GPI(-) HSPCs that evaded immune attack against HSPCs. However, which mechanisms underlie the selection of GPI(-) HSPCs as well as their overwhelming clonal expansion remains unclear. Ancestral or secondary somatic mutations in GPI(-) HSPCs contribute to the clonal expansion of the aberrant HSPCs in certain patients with PNH; however, it remains unclear whether such driver mutations are responsible for clonal expansion of all patients. Increased sensitivity to TGF-β in GPI(-) HSPCs partly explains the predominance of GPI(-) erythrocytes in immune-mediated BM failure. CD4⁺ T cells specific to antigens presented by HLA-DR15 on HSPCs also contribute to the immune escape of GPI(-) HSPCs. Studying the evolution of HSPCs in AA and PNH will yield further information for understanding human autoimmunity and stem cell biology.