Blood, 15 February 2003, Vol. 101, No. 4, pp. 1210-1210
Stem cell damage, adaptation, and leukemogenesis in Fanconi
anemia
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 Fancc
knockout 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.
Grover C. Bagby, Jr
OHSU Cancer
Institute
