A Game of Clones: The Complex Interplay of Aplastic Anaemia, Myelodysplastic Syndrome, and Paroxysmal Nocturnal Haemoglobinuria

Abstract

Although idiopathic aplastic anaemia (AA), myelodysplastic syndrome (MDS), and paroxysmal nocturnal haemoglobinuria (PNH) are all associated with bone marrow failure, they have traditionally been understood as distinct diseases with sharply contrasting pathophysiologies. These three disorders show considerable overlap. In 10% of cases of MDS the bone marrow is hypocellular, resembling AA, while glycophosphatidylinositol-deficient PNH cells can be detected in up to 5% of MDS and in >50% of AA patients. Results of recent studies offer a resolution to this overlap: MDS pathogenesis commonly has an autoimmune component and clonal haematopoiesis can be demonstrated in most cases of AA. Two explanations have arisen to explain the association of PNH with these disorders. It is hypothesised that PNH haematopoietic stem cells are relatively resistant to T cell attack and therefore have a competitive advantage in this context. Alternatively, it has been demonstrated that mutations associated with MDS are commonly present in PNH stem cells; such mutations could provide the PNH clone with an autonomous growth advantage. The authors suggest that these mechanisms may be necessary for the development of PNH in all cases, even when PNH occurs in the absence of MDS or AA. Finally, identification of a PNH clone is a predictive and prognostic biomarker in AA and MDS, adding important information for treatment and follow-up.