Pathogenetic theories of bone marrow failure as a result of interaction of the HSC compartment with the immune system. (A) Various triggers of a cytotoxic T-lymphocyte reaction in AA. (B) Immune attack against a hypothetical initiating event results in endogenous carcinogenesis and de novo acquisition of clonal events. Immune selection pressure can lead to further clonal evolution of secondary MDS after AA. (C) Theoretically, the aberrant clone itself may be a trigger leading to a similar pathogenic escape reaction and a similar outcome. It is also possible that either a nonspecific or an overshooting immune reaction leads to a contraction of the HSPC compartment as seen in AA or hypocellular MDS. Finally, ineffective tumor surveillance reaction fails to prevent clonal evolution analogous to classic or typical MDS. (D) Recent data demonstrate the presence of somatic mutant clones, consistent with CHIP, in patients with otherwise typical AA. In this scenario, immune response may further augment the oligoclonality by the removal of normal HSCs. Depending on the penetrance of somatic CHIP hits, they expand whereas normal cells are eliminated thus leading to hypocellular MDS. Alternatively, upon successful immunosuppression and recovery of the normal HSCs, the mutant clones are diluted out by expanded normal HSCs.