From bone marrow failure to myeloid malignancies: Multi-dimensional mechanistic insights and therapeutic perspectives

Bone marrow failure syndromes (BMFS) are heterogeneous inherited and acquired disorders characterized by impaired hematopoiesis and an increased risk of myelodysplastic neoplasms (MDS) and acute myeloid leukemia (AML). This review integrates current evidence into a stress–selection–evolution framework for malignant transformation. Cell-intrinsic defects in genome maintenance, telomere homeostasis, ribosome biogenesis, and proteostasis, together with immune-mediated injury and inflammatory niche remodeling, reduce hematopoietic stem-cell fitness and activate stress-response programs. Sustained hematopoietic pressure then selects clones that restore cellular fitness or evade injury; although initially adaptive, some of these clones provide a substrate for subsequent leukemogenic evolution. The stepwise acquisition and cooperation of alterations affecting epigenetic regulation, transcription and differentiation, RNA splicing, and growth signaling ultimately establish clonal dominance and a malignant transcriptional state. This framework helps distinguish compensatory clonal hematopoiesis(CH) from high-risk evolution and supports longitudinal surveillance based on mutation identity, clonal burden, dynamics, and disease context. We further discuss how these insights may inform early interception and precision therapy while emphasizing the need to validate risk models and preventive strategies across BMFS subtypes.