Hypothetical model for inflammation-enhanced malignant transformation in early hematopoiesis. The 3 principle outcomes of HSC divisions are self-renewal, differentiation, and death. The balance between these 3 cell fates is closely regulated to ensure balanced blood cell production over the lifetime of an individual. With increased proliferative history in the HSC compartment, the probability of acquiring genetic alterations (“hits”) in HSCs increases, but efficient counteractive mechanisms (eg, apoptosis, DNA repair) have evolved to remove or correct genetically altered HSCs from the pool (top). It can be hypothesized that under chronic or repetitive inflammation the likelihood of genetic hit acquisition and subsequent accumulation in HSC is increased by two major mechanisms: First, accelerated HSC cycling and self-renewal enhances the statistical probability of acquiring mutations during DNA replication. Second, genetically altered HSC clones are rescued by signals delivered from the inflammatory environment. Persistent and aberrant self-renewal of the respective HSC clone might enhance occurrence of further genetic hits, eventually, resulting in the development of HSC neoplasia, for example, acute myeloid leukemia/myelodysplastic syndrome (AML/MDS, bottom).