Somatic pathways of clonal expansion in IBMFSs. HSPCs in IBMFSs have impaired baseline global fitness compared with normal HSPCs. Somatic mutations can lead to the development of CH by improving fitness over the germline state. Somatic normalization occurs through correction of the fitness defect by reversion or compensation, with intact tumor-suppressor pathways. Improvement in fitness is limited to a maximum of wild-type levels, and leukemic potential is low. In contrast, somatic transformation occurs through loss of fitness sensing, with bypass of tumor-suppressor pathways. Improvement in fitness is theoretically unlimited, and leukemic potential is high.