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Prepublished online as a Blood First Edition Paper on October 10, 2002; DOI 10.1182/blood-2002-08-2404.
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Blood, 15 February 2003, Vol. 101, No. 4, pp. 1299-1307
GENE THERAPY
Retroviral-mediated expression of recombinant Fancc enhances
the repopulating ability of Fancc /
hematopoietic stem cells and decreases the risk of clonal
evolution
Laura S. Haneline,
Xiaxin Li,
Samantha L. M. Ciccone,
Ping Hong,
Yanzhu Yang,
Hal E. Broxmeyer,
Suk-Hee Lee,
Attilio Orazi,
Edward F. Srour, and
D. Wade Clapp
From the Department of Pediatrics, Herman B Wells
Center for Pediatric Research, Departments of Biochemistry,
Microbiology/Immunology, Pathology, and Medicine, Walther Oncology
Center, Indiana University School of Medicine, Indianapolis, IN; and
Walther Cancer Institute, Indianapolis, IN.
Fanconi anemia (FA) is a chromosomal instability disorder
characterized by a progressive bone marrow (BM) failure and an
increased incidence of myeloid leukemias. Children with FA are
currently being enrolled in clinical trials to evaluate the safety of
retroviral-mediated gene transfer. Previously, we used
Fancc / mice to show that
Fancc/ hematopoietic stem cells (HSCs) have
a profound defect in repopulating ability. Here, we examined whether
retroviral-mediated gene transfer of recombinant
Fancc (rFancc) would restore the repopulating
ability of Fancc/ HSC to wild-type
levels. Fancc/ HSCs transduced with a
retrovirus encoding rFancc exhibited a repopulating ability that
approached wild-type levels. Interestingly, ~30% of primary
recipients (7 of 22) transplanted with uncorrected Fancc/ cells developed a range of
hematopoietic abnormalities including pancytopenia and BM hypoplasia
similar to individuals with FA. Hematopoietic abnormalities were
detected in only 1 of 22 mice transplanted with
Fancc/ cells transduced with a retrovirus
encoding rFancc. Moreover, several mice with hematopoietic defects had
progenitors that displayed a marked resistance to IFN- , TNF- , and
MIP-1 compared to both Fancc/
progenitors, which are uniquely hypersensitive to these cytokines, and
wild-type progenitors. These data are analogous to studies using
progenitors from patients with myelodysplasia and provide functional
support for clonal evolution in these mice. Collectively, these data
show that gene transfer can enhance HSC repopulating ability and
suppresses the tendency for clonal evolution. These studies also reveal
potential detrimental effects of ex vivo manipulation for untransduced
Fancc/ HSCs.
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