Clonality of the stem cell compartment during evolution of myelodysplastic syndromes and other bone marrow failure syndromes

Clonal hematopoiesis, observed in certain forms of marrow failure including aplastic anemia (AA), may be due to stem cell depletion. Alternatively, oligoclonality may be a result of recruitment of a preexisting defective clone, such as in paroxysmal nocturnal hemoglobinuria (PNH) or myelodysplastic syndromes (MDS). In PNH, exogenous permissive factors may be required for dominance of the abnormal clone, while in MDS, stem cells undergo transformation steps leading to a growth advantage. Stem or multipotent progenitor cell involvement in PNH is evidenced by long-term persistence of a clonal defect and its presence in all blood cells. In MDS, some clonal aberrations may have a ‘founder-effect’ and additional defects are secondary. Metaphase cytogenetics measures the proportion of clonal cells within dividing progenitor but not mature cells. Owing to low resolution, lesions can be found in only ∼50% of MDS patients. This shortcoming may be overcome by application of newer technologies such as comparative genomic hybridization and SNP array-based karyotyping (SNP-A). SNP-A facilitates identification of cryptic lesions in bone marrow failure patients with normal or abnormal cytogenetics and allows for detection of loss of heterozygosity as a result of uniparental disomy, a lesion frequently found in MDS.