We hypothesized that clonal evolution would be accompanied by mutations in genes previously identified in de novo MDS and AML. Our results indicate that accelerated telomere attrition in the setting of a decreased HSPC pool is characteristic of early myeloid oncogenesis, specifically chromosome 7 loss, in MDS/AML after SAA, and provides a possible mechanism for development of aneuploidy. Single telomere length analysis confirmed accumulation of short telomere fragments of individual chromosomes. Patients who evolved to MDS and AML showed marked progressive telomere attrition before the emergence of −7. However, mutations in genes associated with MDS/AML were present in only 4 cases.
Thirteen SAA patients were analyzed for acquired mutations in myeloid cells at the time of evolution to −7, and all had a dominant HSPC clone bearing specific acquired mutations. Most patients respond to immunosuppressive therapies, but a minority transform to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), frequently associated with monosomy 7 (–7). The pathophysiology of severe aplastic anemia (SAA) is immune-mediated destruction of hematopoietic stem and progenitor cells (HSPCs).
