PubMed · 11528843
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K Koike. 2001. [Pancytopenia, Fanconi type].. https://pubmed.ncbi.nlm.nih.gov/11528843/
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Fanconi Anemia (FA) is a heritable syndrome characterized by DNA damage repair deficits, frequent malformations and a significantly elevated risk of bone marrow failure, leukemia, and mucosal head and neck squamous cell carcinomas (HNSCC). Hematopoietic stem cell gene therapy can prevent marrow failure and lower leukemia risk, but mucosal gene therapy to lower HNSCC risk remains untested. Major knowledge gaps include an incomplete understanding of how rapidly gene-corrected cellular lineages could spread through the oral epithelium, and which delivery parameters are critical for ensuring efficient gene correction. To answer these questions, we extended an agent-based model of the oral epithelium to include the delivery of gene correction in situ to FA cells and determine the competitive dynamics between cellular lineages with and without gene correction. We found that only gene-corrected lineages with substantial proliferative advantages (probability of resisting displacement out of the basal layer [Formula: see text]) could spread on clinically relevant timelines, and that these lineages were initially at high risk of loss in the generations following correction. Delivering gene correction to many cells minimizes the risk of loss, while delivery to many distinct locations within a tissue maximizes the rate of spread. To determine the impact of mucosal gene therapy in preventing the clonal expansion of pre-cancerous mutations, we compared the expected burden of TP53 mutations in simulated tissue sections with and without gene correction. We found that when FA cells have elevated genome instability or a TP53-dependent proliferative advantage, gene correction can substantially reduce the accumulation of pro-tumorigenic mutations. This model illustrates the power of computational frameworks to identify critical determinants of therapeutic success to enable experimental optimization and support novel and effective gene therapy applications.
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Fanconi anemia (FA) is a rare hereditary disease characterized by bone marrow failure and developmental anomalies; a high incidence of myelodysplasia (MDS), acute nonlymphocytic leukemia (AML), and solid tumors; and cellular hypersensitivity to cross-linking agents. The genetic basis of FA is mutations in any one of the known FA genes. The function of the proteins is largely unknown, but many form complexes with each other, and in one canonical "pathway," eight of the known FA proteins bind together in a complex and monoubiquitinate FANCD2, a protein not present in the core complex. Monoubiquitinated FANCD2 translocates to damage-induced nuclear foci containing BRCA1, BRCA2, and Rad51, thereby protecting the genome. Because hypersensitivity to genotoxic stress is a feature of all somatic cells, this aspect of FA protein function cannot account for the nearly universal development of bone marrow failure. There is strong in vitro and in vivo evidence that at least some of the FA proteins promote survival signaling pathways in hematopoietic cells by forming complexes with signaling molecules. Because associations with heat shock proteins occur in this context, we suggest that these proteins function as co-chaperones and scaffolds that organize proper responses to a wide variety of extracellular cues, some global, and some specific for hematopoietic cells.