Models for BMF in FA. (A) The accumulation of DNA damage in the HSC pool leads to p53-dependent HSC depletion by diminishing the ability of HSCs to proliferate and self-renew. Endogenously generated aldehydes are an important source of such damage. (B) The molecular basis for cytokine overproduction and hypersensitivity by FA cells remains unclear. However, some FA proteins were proposed to have a direct role in hematopoiesis and to regulate the response to inflammatory signals, independent of DNA repair. (C) Reconciliation of the roles of FA proteins in hematopoiesis. A defect in DNA repair could be the initiating event that would lead to cell death, tissue injury, and the production of inflammatory cytokines. These could then contribute to bone marrow dysfunction in a number of ways. TNF-α and IFN-γ can cause apoptosis in stem cells and progenitors, mediated, for example, by the Fas receptor.⁷⁸  Alternatively, TNF-α could produce additional DNA damage by the induction of reactive molecules, like ROS.⁸⁵  Finally, inflammatory cytokines like TNF-α and IFN-γ have classically been considered to inhibit HSC and limit stem cell function. However, recent studies are challenging this view and propose a role for inflammatory signals in the direct regulation of HSCs.⁸⁶  It is conceivable that these signals could lead to the differentiation of HSCs, either directly or indirectly, causing them to encounter new DNA damage in the context of replication.