Acquired dysfunction of FA proteins, a potential progression factor in secondary AML/MDS. We propose that FANCA dysfunction was acquired by an evolving clone of initiated hematopoietic stem cells. As shown on the right, an early FA-inactivating event would render the cell hypersensitive to apoptotic stimuli, resulting in apoptosis. However, as shown on the left, if a similar event occurred in an already initiated cell, the cell could resist apoptotic cues. The FA defect would then contribute to genetic instability and lead to multiple cytogenetic defects in the evolving clone. HSC indicates hematopoietic stem cell; FA, any FA protein or factor that enhances FA protein function.