Biallelic inactivation of any one of 7 genes results in Fanconi anemia (FA), a rare disease that predisposes children and adults to bone marrow failure, endocrinopathies, myelodysplasia (MDS), acute myelogenous leukemia (AML), and epithelial malignancies. There exists evidence that the FA proteins participate together physically and functionally in the nucleus to effect one or more types of DNA repair pathway. Equally strong is evidence that the FA proteins are multifunctional and participate independently in survival signaling pathways in hematopoietic cells (mutant cells are proapoptotic). What role does failure of each of these functions play in outgrowth of leukemic clones?
In this issue, Haneline and colleagues (page 1299) tackle this question and resolve 4 unanswered questions about murine models of FA. First, can one develop a model of marrow failure without exposing the mice to alkylating agents? Yes, by transplanting stem cells of Fanccknockout mice into lethally irradiated recipients. Second, are stem cells as hypersensitive to extracellular apoptotic cues? Yes. Stem cells of the Fancc−/− mice were intolerant of ex vivo manipulation. Third, do mice show suggestive evidence of clonal adaptation, MDS, or AML? Yes. Some of the mice with low levels of chimerism later developed increasing fractional repopulation by the mutant cells and their progeny were resistant to apoptotic cues ex vivo. Fourth, do mice receiving transplants of mutant stem cells corrected by a Fancc-expressing retroviral vector develop hematopoietic defects? Yes, but at a rate much lower than that of the mice receiving uncorrected cells. Implication? Gene therapy may not only fix the bone marrow failure syndrome in FA patients but prevent MDS and AML as well. Clearly, many questions remain for us all to tackle, but Haneline and her group should be congratulated for solving so many problems in this field with one carefully done study.
