Clonal evolutionary chart of bone marrow failure syndromes over time for AA and primary MDS. Normal hematopoiesis would, if not influenced by a disease pathology, be expected to remain relatively stable with only a slow age-related decline. (A) CHIP, random or pathogenic aberrant myeloid clones, or idiopathic triggers can induce an immune reaction against the hematopoietic stem and progenitor cell (HSPC) compartment leading to AA with contraction of the HSCP pool. Transient or persistent benign clonality may result from CHIP. Either CHIP or another de novo aberrant clone may be an origin of clonal progression (eg, by the acquisition of additional genetic hits resulting in post-AA secondary MDS). (B) Similarly, primary MDS including its classic (hypercellular or normocellular) or atypical (hypocellular) forms can evolve from a slow-driving preexisting CHIP clone or an aberrant de novo somatic hit. Hypocellularity may be a result of immune attack stemming from a tumor surveillance reaction similar to idiopathic AA.