Disrupted Signaling through the Fanconi Anemia Pathway Leads to Dysfunctional Hematopoietic Stem Cell Biology: Underlying Mechanisms and Potential Therapeutic Strategies

Figure 2

Potential novel therapeutic approaches for the prevention of FA HSC depletion. The potential physiologic mediators of FA HSC depletion, including replicative stress, TNF-α, ROS, lipopolysaccharide (LPS), and reactive aldehydes, are depicted as green arrows. Exposure of FA HSCs to these agents/conditions would be predicted to result in DNA damage and ultimately loss of the cell via apoptosis or senescence. Novel therapeutic modalities that directly target these HSC-depleting stimuli are shown in red. Controlling dietary consumption of certain food types (e.g., alcohol) may reduce the production of high levels of reactive aldehyde species in FA patients. Intracellular ROS could be decreased via treatment with antioxidants or ROS scavengers. Proinflammatory cytokine signaling could be targeted by interfering with ligand-receptor binding (e.g., using etanercept or infliximab to block interaction of TNF-α with its receptors) or by inhibiting downstream signaling cascades, as demonstrated for HOXB4 overexpression in the context of TNF-α signaling. Finally, gene therapy approaches offer the possibility of restoring expression of a functional FA gene into patient HSCs.