Topics in Pediatric Leukemia -- Fanconi's Anemia: New Insights

Noah Federman, MD; Kathleen M. Sakamoto, MD, PhD

In This Article

New Insights Into the Genetic and Molecular Basis of FA

The inheritance pattern of FA is autosomal recessive with carrier rates of 1 in 300 in Europe and in the United States,[7] and an increased frequency in Ashkenazi Jews and Afrikaners (estimated at 1 in 90).[8] There is a wide heterogeneity in the genetic basis of FA. Somatic cell-fusion studies have defined 8 complementation groups: FANCA, B, C, D1 (identical to BRCA2), D2, E, F, and G. Seven genes have been cloned, with FANCA being the most common mutation, present in about 70% of FA patients.[9]

Recent studies have shown that these protein products form large multiprotein nuclear complexes, protect against genotoxic stress, contribute to DNA repair, and participate in survival-signaling pathways in hematopoietic cells. Genotoxic stress causing DNA damage activates the FA pathway. The FANCA, C, E, F, and G protein products form a nuclear complex, which is involved in the ubiquitination of FANCD2 to FANCD2-UB. This ubiquitinated protein then colocalizes with the DNA damage-response proteins BRCA1, BRCA2, and RAD51, which promote homologous recombination repair and contribute to genomic stability. It is hypothesized, therefore, that patients who have mutations in the various FA proteins become hypersensitive to DNA crosslinking agents, thereby developing chromosomal instability and cancer.[10,11]

The mechanism(s) by which the FANC protein complex causes bone marrow failure is/are currently unknown. Murine models of FA have hematopoietic progenitors that are hypersensitive to interferon-gamma. Previous work has shown that in hematopoietic progenitor cells, FANCC associates with Hsp70 and PKR when exposed to interferon-gamma or tumor necrosis factor-alpha; this causes excessive apoptosis.[12] Further studies have shown that gene transfer of wild-type FA gene into FA-affected hematopoietic cells increases cell growth and survival, and normalizes sensitivity to DNA crosslinking agents.[13]


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